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1.
Cell Tissue Res ; 394(1): 1-16, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37016180

ABSTRACT

Senescence is a widely appreciated tumour suppressive mechanism, which acts as a barrier to cancer development by arresting cell cycle progression in response to harmful stimuli. However, senescent cell accumulation becomes deleterious in aging and contributes to a wide range of age-related pathologies. Furthermore, senescence has beneficial roles and is associated with a growing list of normal physiological processes including wound healing and embryonic development. Therefore, the biological role of senescent cells has become increasingly nuanced and complex. The emergence of sophisticated, next-generation profiling technologies, such as single-cell RNA sequencing, has accelerated our understanding of the heterogeneity of senescence, with distinct final cell states emerging within models as well as between cell types and tissues. In order to explore data sets of increasing size and complexity, the senescence field has begun to employ machine learning (ML) methodologies to probe these intricacies. Most notably, ML has been used to aid the classification of cells as senescent, as well as to characterise the final senescence phenotypes. Here, we provide a background to the principles of ML tasks, as well as some of the most commonly used methodologies from both traditional and deep ML. We focus on the application of these within the context of senescence research, by addressing the utility of ML for the analysis of data from different laboratory technologies (microscopy, transcriptomics, proteomics, methylomics), as well as the potential within senolytic drug discovery. Together, we aim to highlight both the progress and potential for the application of ML within senescence research.


Subject(s)
Cellular Senescence , Neoplasms , Humans , Cellular Senescence/genetics , Aging/metabolism , Neoplasms/genetics , Phenotype , Cell Division
2.
Biomedicines ; 10(12)2022 Dec 02.
Article in English | MEDLINE | ID: mdl-36551868

ABSTRACT

Melanocytes reside within the basal epidermis of human skin, and function to protect the skin from ultraviolet light through the production of melanin. Prolonged exposure of the skin to UV light can induce irreparable DNA damage and drive cells into senescence, a sustained cell cycle arrest that prevents the propagation of this damage. Senescent cells can also be detrimental and contribute to skin ageing phenotypes through their senescence-associated secretory phenotype. Senescent cells can act in both an autocrine and paracrine manner to produce widespread tissue inflammation and skin ageing. Recently, melanocytes have been identified as the main senescent cell population within the epidermis and have been linked to a variety of skin ageing phenotypes, such as epidermal thinning and the presence of wrinkles. However, the literature surrounding melanocyte senescence is limited and tends to focus on the role of senescence in the prevention of melanoma. Therefore, this review aims to explore the current understanding of the contribution of senescent melanocytes to human skin ageing.

3.
Aging (Albany NY) ; 14(10): 4220-4246, 2022 05 16.
Article in English | MEDLINE | ID: mdl-35580013

ABSTRACT

Senescence occurs in response to a number of damaging stimuli to limit oncogenic transformation and cancer development. As no single, universal senescence marker has been discovered, the confident classification of senescence induction requires the parallel assessment of a series of hallmarks. Therefore, there is a growing need for "first-pass" tools of senescence identification to streamline experimental workflows and complement conventional markers. Here, we utilise a high content, multidimensional phenotypic profiling-based approach, to assess the morphological profiles of senescent cells induced via a range of stimuli. In the context of senescence, we refer to these as senescence-associated morphological profiles (SAMPs), as they facilitate distinction between senescent and proliferating cells. The complexity of the profiles generated also allows exploration of the heterogeneity both between models of senescence and within an individual senescence model, providing a level of insight at the single cell level. Furthermore, we also demonstrate that these models are applicable to the assessment of senescence in vivo, which remains a key challenge for the field. Therefore, we believe SAMPs has the potential to serve as a useful addition in the repertoire of senescence researchers, either as a first-pass tool or as part of the established senescence hallmarks.


Subject(s)
Cellular Senescence , Neoplasms , Biomarkers , Carcinogenesis , Humans , Neoplasms/genetics , Oncogenes
4.
Aging Cell ; 20(3): e13318, 2021 03.
Article in English | MEDLINE | ID: mdl-33547862

ABSTRACT

Senescence, a state of stable growth arrest, plays an important role in ageing and age-related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up-regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down-regulates p16 levels and increases the pool of p16- p21- 'reversed' cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence.


Subject(s)
Cellular Senescence , Early Growth Response Protein 2/metabolism , Adolescent , Adult , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Epithelial Cells/cytology , Epithelial Cells/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Knockdown Techniques , Humans , Mammary Glands, Human/cytology , Protein Binding , RNA, Small Interfering/metabolism , Retinoblastoma Protein/metabolism , Tumor Suppressor Protein p53/metabolism , Up-Regulation , Young Adult
5.
Front Immunol ; 10: 1721, 2019.
Article in English | MEDLINE | ID: mdl-31417543

ABSTRACT

Non-typeable Haemophilus influenzae (NTHi) is a frequent cause of lower respiratory tract infection in people with chronic obstructive pulmonary disease (COPD). Pellino proteins are a family of E3 ubiquitin ligases that are critical regulators of TLR signaling and inflammation. The aim of this study was to identify a role for Pellino-1 in airway defense against NTHi in the context of COPD. Pellino-1 is rapidly upregulated by LPS and NTHi in monocyte-derived macrophages (MDMs) isolated from individuals with COPD and healthy control subjects, in a TLR4 dependent manner. C57BL/6 Peli1-/- and wild-type (WT) mice were subjected to acute (single LPS challenge) or chronic (repeated LPS and elastase challenge) airway inflammation followed by NTHi infection. Both WT and Peli1-/- mice develop airway inflammation in acute and chronic airway inflammation models. Peli1-/- animals recruit significantly more neutrophils to the airway following NTHi infection which is associated with an increase in the neutrophil chemokine, KC, in bronchoalveolar lavage fluid as well as enhanced clearance of NTHi from the lung. These data suggest that therapeutic inhibition of Pellino-1 may augment immune responses in the airway and enhance bacterial clearance in individuals with COPD.


Subject(s)
Haemophilus Infections/immunology , Haemophilus influenzae/immunology , Macrophages/immunology , Monocytes/immunology , Nuclear Proteins/immunology , Pneumonia, Bacterial/immunology , Ubiquitin-Protein Ligases/immunology , Animals , Chemokine CXCL1/genetics , Chemokine CXCL1/immunology , Haemophilus Infections/genetics , Haemophilus Infections/pathology , Humans , Macrophages/pathology , Mice , Mice, Knockout , Monocytes/pathology , Nuclear Proteins/genetics , Pneumonia, Bacterial/genetics , Pneumonia, Bacterial/pathology , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/pathology , Ubiquitin-Protein Ligases/genetics
6.
Acta Biomater ; 78: 89-97, 2018 09 15.
Article in English | MEDLINE | ID: mdl-30092377

ABSTRACT

Cell-cell communication plays a critical role in a myriad of processes, such as homeostasis, angiogenesis, and carcinogenesis, in multi-cellular organisms. Monolayer cell models have notably improved our understanding of cellular interactions. However, the cultured cells on the planar surfaces adopt a two-dimensional morphology, which poorly imitates cellular organization in vivo, providing physiologically-irrelevant cell responses. Non-planar surfaces comprising various patterns have demonstrated great abilities in directing cellular growth and producing different cell morphologies. In recent years, a few topographical substrates have provided valuable information about cell-cell signalling, however, none of these studies have reported a three-dimensional (3D) cell morphology. Here, we introduce a structurally tunable topographical platform that can maintain cell coupling while inducing a true 3D cell morphology. Optical imaging and fluorescence recovery after photobleaching are used to illustrate these capabilities. Our analyses suggest that the intercellular signalling on the present platform, which we propose is mainly through gap junctions, is comparable to that in natural tissue. STATEMENT OF SIGNIFICANCE: A better understanding of direct cellular communication can help treating neurological diseases and cancers, which may be caused by dysfunctional intercellular signaling. To investigate cell-cell contact, cells are conventionally plated onto planar surfaces, where they flatten and adopt a two-dimensional cell morphology. These unrealistic models are physiologically-irrelevant since cells exhibit a three-dimensional (3D) shape in the body. Therefore, porous scaffolds and topographical surfaces, capable of inducing various cell morphologies, have been introduced, in which the latter is more desirable for sample imaging and screening. However, the few non-planar substrates used to study cell coupling have not produced a 3D cell shape. Here, we present a tunable culture platform that can control direct cell-cell communication while maintaining true 3D cell morphologies.


Subject(s)
Cell Communication , Cell Shape , Tissue Scaffolds/chemistry , Animals , Cattle , Cell Nucleus/metabolism , Fibroblasts/cytology , Fibroblasts/ultrastructure , Fluorescence Recovery After Photobleaching , Microfluidics
7.
Sci Rep ; 6: 30463, 2016 07 27.
Article in English | MEDLINE | ID: mdl-27461741

ABSTRACT

Surface wrinkled particles are ubiquitous in nature and present in different sizes and shapes, such as plant pollens and peppercorn seeds. These natural wrinkles provide the particles with advanced functions to survive and thrive in nature. In this work, by combining flow lithography and plasma treatment, we have developed a simple method that can rapidly create wrinkled non-spherical particles, mimicking the surface textures in nature. Due to the oxygen inhibition in flow lithography, the non-spherical particles synthesized in a microfluidic channel are covered by a partially cured polymer (PCP) layer. When exposed to plasma treatment, this PCP layer rapidly buckles, forming surface-wrinkled particles. We designed and fabricated various particles with desired shapes and sizes. The surfaces of these shapes were tuned to created wrinkle morphologies by controlling UV exposure time and the washing process. We further demonstrated that wrinkles on the particles significantly promoted cell attachment without any chemical modification, potentially providing a new route for cell attachment for various biomedical applications.


Subject(s)
Fibroblasts/cytology , Polymers/chemistry , Animals , Cattle , Cell Adhesion , Fibroblasts/ultrastructure , Microfluidics , Microscopy, Confocal , Photoelectron Spectroscopy , Surface Properties , Time Factors , Ultraviolet Rays
8.
Bioorg Med Chem Lett ; 25(17): 3495-500, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26142947

ABSTRACT

The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aß42 lowering maintained in both transgenic mouse and rat.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/pharmacokinetics , Animals , Biological Availability , Mice , Mice, Transgenic , Rats
9.
Bioorg Med Chem Lett ; 25(17): 3488-94, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26212776

ABSTRACT

Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aß42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aß42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aß42 levels.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Animals , Drug Discovery , Macaca mulatta , Mice , Mice, Transgenic , Rats , Rats, Sprague-Dawley
10.
ACS Med Chem Lett ; 5(4): 340-5, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24900838

ABSTRACT

The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.

11.
Bioorg Med Chem Lett ; 22(9): 3140-6, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22497762

ABSTRACT

Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aß42 IC(50) in cell-based assays and reduced affinity for the hERG channel.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Trans-Activators/metabolism , Triazoles/pharmacology , Amides/chemistry , Amides/pharmacology , Amyloid beta-Peptides , Cell Line , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Lactams , Structure-Activity Relationship , Transcriptional Regulator ERG , Triazoles/chemistry
12.
Bioorg Med Chem Lett ; 22(9): 3203-7, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22483609

ABSTRACT

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.


Subject(s)
Amides/chemical synthesis , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Alzheimer Disease/drug therapy , Amides/pharmacology , Amyloid beta-Peptides/biosynthesis , Animals , Brain/drug effects , Brain/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Mice , Peptide Fragments/biosynthesis
13.
Bioorg Med Chem Lett ; 21(13): 4083-7, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21616665

ABSTRACT

Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aß42 in Sprague-Dawley rats.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Triazoles/chemical synthesis , Triazoles/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazoles/metabolism
15.
Sci Signal ; 3(145): ra76, 2010 Oct 26.
Article in English | MEDLINE | ID: mdl-20978237

ABSTRACT

One function of phosphoinositide 3-kinase α (PI3Kα), which generates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)], is its regulation of angiogenesis in the developing embryo and in pathological situations. ARAP3 is a PtdIns(3,4,5)P(3)- and Rap-activated guanosine triphosphatase (GTPase)-activating protein (GAP) for the small GTPases RhoA and Arf6. Here, we show that deleting Arap3 in the mouse caused embryonic death in mid-gestation due to an endothelial cell-autonomous defect in sprouting angiogenesis. Explants taken at a developmental stage at which no defect was yet present reproduced this phenotype ex vivo, demonstrating that the defect was not secondary to hypoxia, placental defects, or organ failure. In addition, knock-in mice expressing an ARAP3 point mutant that cannot be activated by PtdIns(3,4,5)P(3) had angiogenesis defects similar to those of Arap3(-/-) embryos. Our work delineates a previously unknown signaling pathway that controls angiogenesis immediately downstream of PI3Kα through ARAP3 to the Rho and Arf family of small GTPases.


Subject(s)
Class Ia Phosphatidylinositol 3-Kinase/metabolism , Embryo, Mammalian/metabolism , GTPase-Activating Proteins/metabolism , Neovascularization, Physiologic/physiology , Phosphatidylinositol Phosphates/metabolism , Second Messenger Systems/physiology , Animals , Class Ia Phosphatidylinositol 3-Kinase/genetics , Embryo Loss/genetics , Embryo Loss/metabolism , GTPase-Activating Proteins/genetics , Gene Deletion , Mice , Phosphatidylinositol Phosphates/genetics , Point Mutation
16.
Bioorg Med Chem Lett ; 20(7): 2279-82, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20207146

ABSTRACT

The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Peptide Fragments/antagonists & inhibitors , Purines/chemistry , Purines/therapeutic use , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Peptides/metabolism , Animals , Humans , Mice , Mice, Transgenic , Peptide Fragments/metabolism , Purines/pharmacology , Receptors, Notch/metabolism , Structure-Activity Relationship
17.
Bioorg Med Chem Lett ; 20(2): 755-8, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-20005099

ABSTRACT

We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.


Subject(s)
Acetates/chemistry , Amyloid Precursor Protein Secretases/metabolism , Fluorine/chemistry , Piperidines/chemistry , Acetates/chemical synthesis , Acetates/pharmacokinetics , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Diazonium Compounds/chemistry , Disease Models, Animal , Mice , Mice, Transgenic , Peptide Fragments/genetics , Peptide Fragments/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Receptors, Notch/metabolism
18.
Bioorg Med Chem Lett ; 20(3): 1269-71, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20022243

ABSTRACT

The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Piperazines/chemistry , Pyrimidines/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/physiology , Cell Line, Tumor , HeLa Cells , Humans , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Piperazines/pharmacology , Pyrimidines/pharmacology
19.
Glycobiology ; 19(12): 1554-62, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19729382

ABSTRACT

Inefficient glycosylation caused by defective synthesis of lipid-linked oligosaccharide donor results in multi-systemic syndromes known as congenital disorders of glycosylation type I (CDG-I). Strong loss of function mutations are embryonic lethal, patients with partial losses of function are occasionally born but are very ill, presenting with defects in virtually every tissue. CDG-I clinical expression varies considerably and ranges from very mild to severe, and the underlying cause of the variable clinical features is not yet understood. We postulate that accompanying defects in an individual's genetic background enhance the severity of CDG-I clinical phenotypes. Since so many protein structures and functions are compromised in CDG-I illnesses, the gene products that are dependent on N-linked glycosylation which cause lethality or particular symptoms are difficult to resolve. The power of genetic silencing that is a characteristic of C. elegans has allowed us to systematically dissect the complex glycosylation phenotype observed in CDG-I patients into specific glycan-dependent gene products. To accomplish this, we inhibited glycosylation with a sub-phenotypic dose of tunicamycin, reduced single genes by RNA interference, and then sought loci where the combination caused a synthetic or dramatically enhanced phenotype. This screen has identified genes in C. elegans that require N-linked glycans to function properly as well as candidate gene homologues that may enhance the clinical severity of CDG-I disorders in humans.


Subject(s)
Caenorhabditis elegans , Carbohydrate Metabolism, Inborn Errors/genetics , Carbohydrate Metabolism, Inborn Errors/pathology , Chromosome Mapping/methods , Disease Models, Animal , Animals , Anti-Bacterial Agents/pharmacology , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Drug Resistance/genetics , Genetic Loci , Glycosylation/drug effects , Humans , Phenotype , RNA Interference/physiology , RNA, Small Interfering/pharmacology , Tunicamycin/pharmacology
20.
Bioorg Med Chem Lett ; 19(7): 2053-8, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19268585

ABSTRACT

We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Histone Deacetylase Inhibitors , Organophosphonates/pharmacokinetics , Repressor Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Histone Deacetylase 1 , Histone Deacetylase 2 , Histone Deacetylases/metabolism , Mice , Mice, Nude , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Repressor Proteins/metabolism , Transplantation, Heterologous
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