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  1. Article ; Online: The potential of the proteome to predict fracture.

    Chai, Ryan C / Blank, Robert D

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2024  Volume 39, Issue 3, Page(s) 195–196

    MeSH term(s) Humans ; Proteome ; Hip Fractures
    Chemical Substances Proteome
    Language English
    Publishing date 2024-03-15
    Publishing country England
    Document type Editorial ; Comment
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1093/jbmr/zjae005
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    Zs.A 2142: Show issues Location:
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  2. Article ; Online: Single-Cell RNA Sequencing: Unravelling the Bone One Cell at a Time.

    Chai, Ryan C

    Current osteoporosis reports

    2022  Volume 20, Issue 5, Page(s) 356–362

    Abstract: Purpose of review: Bone is a complex tissue populated by a highly heterogeneous mix of cell types in different compartments. The endosteal compartment is a key site for bone remodelling and provides a supportive microenvironment to harbour ... ...

    Abstract Purpose of review: Bone is a complex tissue populated by a highly heterogeneous mix of cell types in different compartments. The endosteal compartment is a key site for bone remodelling and provides a supportive microenvironment to harbour haematopoietic and mesenchymal stem cells, as well as cancer cells that grow in bone. The purpose of this review is to summarize recent findings of studies in bone using single-cell RNA sequencing and emergent spatial RNA sequencing to describe different bone-resident cell types and their molecular programs.
    Recent findings: Single-cell RNA sequencing identified novel and transcriptionally distinct cell clusters within different bone cell lineages, including MSCs, osteoblasts, chondrocytes, fibroblasts, osteoclasts and cells of the vasculature. Spatial transcriptomics methods provide information on the localization of the different cell populations. Single-cell transcriptomics provided valuable insights into long-standing knowledge gaps in the cellular heterogeneity of bone-resident cells in unprecedented detail, paving the way for studies to further investigate the different cell populations and to develop cell-based therapies for bone diseases.
    MeSH term(s) Cell Lineage ; Humans ; Mesenchymal Stem Cells/metabolism ; Osteoblasts/metabolism ; Osteocytes ; Sequence Analysis, RNA
    Language English
    Publishing date 2022-08-02
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186581-4
    ISSN 1544-2241 ; 1544-1873
    ISSN (online) 1544-2241
    ISSN 1544-1873
    DOI 10.1007/s11914-022-00735-w
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  3. Article ; Online: Visualisation of tumour cells in bone in vivo at single-cell resolution.

    Chai, Ryan C / McDonald, Michelle M

    Bone

    2021  Volume 158, Page(s) 116113

    Abstract: The skeleton is a common site for the establishment of distant metastases. Once cancers occupy bone, the prognosis is poor as disease recurrence and visceral spread is imminent. Understanding the pathways and cellular interactions, which regulate tumour ... ...

    Abstract The skeleton is a common site for the establishment of distant metastases. Once cancers occupy bone, the prognosis is poor as disease recurrence and visceral spread is imminent. Understanding the pathways and cellular interactions, which regulate tumour cell seeding, dormancy and growth in bone, is pertinent to improving outcomes for patients with advanced cancers. Advances in imaging techniques have facilitated the development of the concept that the behavior of bone marrow resident cells dictates the fate of tumour cells upon arrival in bone. This review summarises recent findings achieved through intravital imaging. It highlights the importance of developing both longitudinal static and acute dynamic data to develop our understanding of tumour cell engraftment, dormancy, activation and the subsequent establishment of metastases. We also describe how imaging techniques have developed our knowledge of the elements that make up the complex bone microenvironment which tumour cells interact with to survive and grow. We also discuss how through combining these imaging insights with single cell RNA sequencing data, we are entering a new era of research which has the power to define the cell-cell interactions which control tumour cell growth in bone.
    MeSH term(s) Bone Neoplasms/diagnostic imaging ; Bone Neoplasms/pathology ; Cell Count ; Humans ; Neoplasms/pathology ; Prognosis ; Radiopharmaceuticals ; Tumor Microenvironment
    Chemical Substances Radiopharmaceuticals
    Language English
    Publishing date 2021-07-15
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2021.116113
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    Zs.MO 332: Show issues

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  4. Article ; Online: ENTRAIN: integrating trajectory inference and gene regulatory networks with spatial data to co-localize the receptor-ligand interactions that specify cell fate.

    Kyaw, Wunna / Chai, Ryan C / Khoo, Weng Hua / Goldstein, Leonard D / Croucher, Peter I / Murray, John M / Phan, Tri Giang

    Bioinformatics (Oxford, England)

    2023  Volume 39, Issue 12

    Abstract: Motivation: Cell fate is commonly studied by profiling the gene expression of single cells to infer developmental trajectories based on expression similarity, RNA velocity, or statistical mechanical properties. However, current approaches do not recover ...

    Abstract Motivation: Cell fate is commonly studied by profiling the gene expression of single cells to infer developmental trajectories based on expression similarity, RNA velocity, or statistical mechanical properties. However, current approaches do not recover microenvironmental signals from the cellular niche that drive a differentiation trajectory.
    Results: We resolve this with environment-aware trajectory inference (ENTRAIN), a computational method that integrates trajectory inference methods with ligand-receptor pair gene regulatory networks to identify extracellular signals and evaluate their relative contribution towards a differentiation trajectory. The output from ENTRAIN can be superimposed on spatial data to co-localize cells and molecules in space and time to map cell fate potentials to cell-cell interactions. We validate and benchmark our approach on single-cell bone marrow and spatially resolved embryonic neurogenesis datasets to identify known and novel environmental drivers of cellular differentiation.
    Availability and implementation: ENTRAIN is available as a public package at https://github.com/theimagelab/entrain and can be used on both single-cell and spatially resolved datasets.
    MeSH term(s) Gene Regulatory Networks ; Ligands ; Cell Differentiation/genetics ; Single-Cell Analysis/methods ; Gene Expression Profiling/methods
    Chemical Substances Ligands
    Language English
    Publishing date 2023-12-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btad765
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    Zs.A 2374: Show issues Location:
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  5. Article ; Online: Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition.

    Kim, Albert S / Taylor, Victoria E / Castro-Martinez, Ariel / Dhakal, Suraj / Zamerli, Amjad / Mohanty, Sindhu / Xiao, Ya / Simic, Marija K / Wen, Jinchen / Chai, Ryan / Croucher, Peter I / Center, Jacqueline R / Girgis, Christian M / McDonald, Michelle M

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2024  Volume 39, Issue 4, Page(s) 484–497

    Abstract: Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of ...

    Abstract Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.
    MeSH term(s) Animals ; Osteoclasts/metabolism ; Osteoclasts/drug effects ; RANK Ligand/antagonists & inhibitors ; RANK Ligand/metabolism ; Denosumab/pharmacology ; Mice ; Bone Resorption/pathology ; Bone Resorption/drug therapy ; Bone Resorption/blood ; Time Factors ; Tartrate-Resistant Acid Phosphatase/metabolism ; Female ; Mice, Inbred C57BL ; Biomarkers/metabolism ; Biomarkers/blood
    Chemical Substances RANK Ligand ; Denosumab (4EQZ6YO2HI) ; Tartrate-Resistant Acid Phosphatase (EC 3.1.3.2) ; Tnfsf11 protein, mouse ; Biomarkers
    Language English
    Publishing date 2024-03-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1093/jbmr/zjae023
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    Zs.A 2142: Show issues Location:
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  6. Article ; Online: Minimally invasive longitudinal intravital imaging of cellular dynamics in intact long bone.

    Bhattacharyya, Nayan Deger / Kyaw, Wunna / McDonald, Michelle M / Dhenni, Rama / Grootveld, Abigail K / Xiao, Ya / Chai, Ryan / Khoo, Weng Hua / Danserau, Linda C / Sergio, C Marcelo / Timpson, Paul / Lee, Woei Ming / Croucher, Peter I / Phan, Tri Giang

    Nature protocols

    2023  Volume 18, Issue 12, Page(s) 3856–3880

    Abstract: Intravital two-photon microscopy enables deep-tissue imaging at high temporospatial resolution in live animals. However, the endosteal bone compartment and underlying bone marrow pose unique challenges to optical imaging as light is absorbed, scattered ... ...

    Abstract Intravital two-photon microscopy enables deep-tissue imaging at high temporospatial resolution in live animals. However, the endosteal bone compartment and underlying bone marrow pose unique challenges to optical imaging as light is absorbed, scattered and dispersed by thick mineralized bone matrix and the adipose-rich bone marrow. Early bone intravital imaging methods exploited gaps in the cranial sutures to bypass the need to penetrate through cortical bone. More recently, investigators have developed invasive methods to thin the cortical bone or implant imaging windows to image cellular dynamics in weight-bearing long bones. Here, we provide a step-by-step procedure for the preparation of animals for minimally invasive, nondestructive, longitudinal intravital imaging of the murine tibia. This method involves the use of mixed bone marrow radiation chimeras to unambiguously double-label osteoclasts and osteomorphs. The tibia is exposed by a simple skin incision and an imaging chamber constructed using thermoconductive T-putty. Imaging sessions up to 12 h long can be repeated over multiple timepoints to provide a longitudinal time window into the endosteal and marrow niches. The approach can be used to investigate cellular dynamics in bone remodeling, cancer cell life cycle and hematopoiesis, as well as long-lived humoral and cellular immunity. The procedure requires an hour to complete and is suitable for users with minimal prior expertise in small animal surgery.
    MeSH term(s) Mice ; Animals ; Bone and Bones/diagnostic imaging ; Intravital Microscopy/methods ; Optical Imaging
    Language English
    Publishing date 2023-10-19
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/s41596-023-00894-9
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  7. Article ; Online: Current trends in the etiology and diagnosis of HPV-related head and neck cancers.

    Chai, Ryan C / Lambie, Duncan / Verma, Mukesh / Punyadeera, Chamindie

    Cancer medicine

    2015  Volume 4, Issue 4, Page(s) 596–607

    Abstract: Human papilloma virus (HPV) infection is a major risk factor for a distinct subset of head and neck squamous cell carcinoma (HNSCC). The current review summarizes the epidemiology of HNSCC and the disease burden, the infectious cycle of HPV, the roles of ...

    Abstract Human papilloma virus (HPV) infection is a major risk factor for a distinct subset of head and neck squamous cell carcinoma (HNSCC). The current review summarizes the epidemiology of HNSCC and the disease burden, the infectious cycle of HPV, the roles of viral oncoproteins, E6 and E7, and the downstream cellular events that lead to malignant transformation. Current techniques for the clinical diagnosis of HPV-associated HNSCC will also be discussed, that is, the detection of HPV DNA, RNA, and the HPV surrogate marker, p16 in tumor tissues, as well as HPV-specific antibodies in serum. Such methods do not allow for the early detection of HPV-associated HNSCC and most cases are at an advanced stage upon diagnosis. Novel noninvasive approaches using oral fluid, a clinically relevant biological fluid, allow for the detection of HPV and cellular alterations in infected cells, which may aid in the early detection and HPV-typing of HNSCC tumors. Noninvasive diagnostic methods will enable early detection and intervention, leading to a significant reduction in mortality and morbidity associated with HNSCC.
    MeSH term(s) Carcinoma, Squamous Cell/diagnosis ; Carcinoma, Squamous Cell/virology ; Cell Transformation, Neoplastic ; Cell Transformation, Viral ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; DNA, Viral/metabolism ; Female ; Head and Neck Neoplasms/diagnosis ; Head and Neck Neoplasms/virology ; Human papillomavirus 16/isolation & purification ; Human papillomavirus 6/isolation & purification ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Oncogene Proteins/metabolism ; Papillomavirus Infections/diagnosis ; RNA, Viral/metabolism ; Saliva/virology
    Chemical Substances Cyclin-Dependent Kinase Inhibitor p16 ; DNA, Viral ; Oncogene Proteins ; RNA, Viral
    Language English
    Publishing date 2015-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 2045-7634
    ISSN (online) 2045-7634
    DOI 10.1002/cam4.424
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  8. Article ; Online: Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors.

    Chai, Ryan C / Vieusseux, Jessica L / Lang, Benjamin J / Nguyen, Chau H / Kouspou, Michelle M / Britt, Kara L / Price, John T

    Molecular oncology

    2017  Volume 11, Issue 5, Page(s) 567–583

    Abstract: Heat shock protein 90 (HSP90) regulates multiple signalling pathways critical for tumour growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not ... ...

    Abstract Heat shock protein 90 (HSP90) regulates multiple signalling pathways critical for tumour growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may be the presence of de novo or acquired resistance within the tumours. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The resultant resistant cell lines maintained their respective levels of resistance (7-240×) in the absence of 17-AAG and were also cross-resistant with other benzoquinone ansamycin HSP90 inhibitors. Expression of members of the histone deacetylase family (HDAC 1, 5, 6) was altered in the resistant cells. To determine whether HDAC activity contributed to resistance, pan-HDAC inhibitors (TSA and LBH589) and the class II HDAC-specific inhibitor SNDX275 were found to resensitize resistant cells towards 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin. Most significantly, resistant cells were also identified as cross-resistant towards structurally distinct HSP90 inhibitors such as radicicol and the second-generation HSP90 inhibitors CCT018159, VER50589 and AUY922. HDAC inhibition also resensitized resistant cells towards these classes of HSP90 inhibitors. In conclusion, we report that prolonged 17-AAG treatment results in acquired resistance of cancer cells towards not just 17-AAG but also to a spectrum of structurally distinct HSP90 inhibitors. This acquired resistance can be inhibited using clinically relevant HDAC inhibitors. This work supports the potential benefit of using HSP90 and HDAC inhibitors in combination within the clinical setting.
    Language English
    Publishing date 2017-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2415106-3
    ISSN 1878-0261 ; 1574-7891
    ISSN (online) 1878-0261
    ISSN 1574-7891
    DOI 10.1002/1878-0261.12054
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    Zs.A 6637: Show issues Location:
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  9. Article ; Online: A pilot study to compare the detection of HPV-16 biomarkers in salivary oral rinses with tumour p16(INK4a) expression in head and neck squamous cell carcinoma patients.

    Chai, Ryan C / Lim, Yenkai / Frazer, Ian H / Wan, Yunxia / Perry, Christopher / Jones, Lee / Lambie, Duncan / Punyadeera, Chamindie

    BMC cancer

    2016  Volume 16, Page(s) 178

    Abstract: Background: Human papilloma virus-16 (HPV-16) infection is a major risk factor for a subset of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). Current techniques for assessing the HPV-16 status ...

    Abstract Background: Human papilloma virus-16 (HPV-16) infection is a major risk factor for a subset of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). Current techniques for assessing the HPV-16 status in HNSCC include the detection of HPV-16 DNA and p16(INK4a) expression in tumor tissues. When tumors originate from hidden anatomical sites, this method can be challenging. A non-invasive and cost-effective alternative to biopsy is therefore desirable for HPV-16 detection especially within a community setting to screen at-risk individuals.
    Methods: The present study compared detection of HPV-16 DNA and RNA in salivary oral rinses with tumor p16(INK4a) status, in 82 HNSCC patients using end-point and quantitative polymerase chain reaction (PCR).
    Results: Of 42 patients with p16(INK4a)-positive tumours, 39 (sensitivity = 92.9 %, PPV = 100 % and NPV = 93 %) had oral rinse samples with detectable HPV-16 DNA, using end-point and quantitative PCR. No HPV-16 DNA was detected in oral rinse samples from 40 patients with p16(INK4a) negative tumours, yielding a test specificity of 100 %. For patients with p16(INK4a) positive tumours, HPV-16 mRNA was detected using end-point reverse transcription PCR (RT-PCR) in 24/40 (sensitivity = 60 %, PPV = 100 % and NPV = 71 %), and using quantitative RT-PCR in 22/40 (sensitivity = 55 %, PPV = 100 % and NPV = 69 %). No HPV-16 mRNA was detected in oral rinse samples from the p16(INK4a)-negative patients, yielding a specificity of 100 %.
    Conclusions: We demonstrate that the detection of HPV-16 DNA in salivary oral rinse is indicative of HPV status in HNSCC patients and can potentially be used as a diagnostic tool in addition to the current methods.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Carcinoma, Squamous Cell/etiology ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; DNA, Viral ; Female ; Genes, Viral ; Head and Neck Neoplasms/etiology ; Human papillomavirus 16/genetics ; Humans ; Male ; Middle Aged ; Papillomavirus Infections/complications ; Papillomavirus Infections/virology ; Polymerase Chain Reaction ; Saliva ; Squamous Cell Carcinoma of Head and Neck
    Chemical Substances Biomarkers, Tumor ; Cyclin-Dependent Kinase Inhibitor p16 ; DNA, Viral
    Language English
    Publishing date 2016-03-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1471-2407
    ISSN (online) 1471-2407
    DOI 10.1186/s12885-016-2217-1
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  10. Article ; Online: Heat-shock factor 1 both positively and negatively affects cellular clonogenic growth depending on p53 status.

    Nguyen, Chau H / Lang, Benjamin J / Chai, Ryan C C / Vieusseux, Jessica L / Kouspou, Michelle M / Price, John T

    The Biochemical journal

    2013  Volume 452, Issue 2, Page(s) 321–329

    Abstract: HSF1 (heat-shock factor 1) is the master regulator of the heat-shock response; however, it is also activated by cancer-associated stresses and supports cellular transformation and cancer progression. We examined the role of HSF1 in relation to cancer ... ...

    Abstract HSF1 (heat-shock factor 1) is the master regulator of the heat-shock response; however, it is also activated by cancer-associated stresses and supports cellular transformation and cancer progression. We examined the role of HSF1 in relation to cancer cell clonogenicity, an important attribute of cancer cells. Ectopic expression or HSF1 knockdown demonstrated that HSF1 positively regulated cancer cell clonogenic growth. Furthermore, knockdown of mutant p53 indicated that HSF1 actions were mediated via a mutant p53-dependent mechanism. To examine this relationship more specifically, we ectopically co-expressed mutant p53(R273H) and HSF1 in the human mammary epithelial cell line MCF10A. Surprisingly, within this cellular context, HSF1 inhibited clonogenicity. However, upon specific knockdown of endogenous wild-type p53, leaving mutant p53(R273H) expression intact, HSF1 was observed to greatly enhance clonogenic growth of the cells, indicating that HSF1 suppressed clonogenicity via wild-type p53. To confirm this we ectopically expressed HSF1 in non-transformed and H-Ras(V12)-transformed MCF10A cells. As expected, HSF1 significantly reduced clonogenicity, altering wild-type p53 target gene expression levels consistent with a role of HSF1 increasing wild-type p53 activity. In support of this finding, knockdown of wild-type p53 negated the inhibitory effects of HSF1 expression. We thus show that HSF1 can affect clonogenic growth in a p53 context-dependent manner, and can act via both mutant and wild-type p53 to bring about divergent effects upon clonogenicity. These findings have important implications for our understanding of HSF1's divergent roles in cancer cell growth and survival as well as its disparate effect on mutant and wild-type p53.
    MeSH term(s) Cell Line ; Cell Line, Tumor ; Cell Transformation, Neoplastic/chemistry ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Clone Cells ; DNA-Binding Proteins/antagonists & inhibitors ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Down-Regulation/genetics ; Female ; Heat Shock Transcription Factors ; Humans ; Mutant Proteins/genetics ; Mutant Proteins/physiology ; Mutation ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics ; Transcription Factors/physiology ; Tumor Stem Cell Assay ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/physiology ; Up-Regulation/genetics
    Chemical Substances DNA-Binding Proteins ; HSF1 protein, human ; Heat Shock Transcription Factors ; Mutant Proteins ; TP53 protein, human ; Transcription Factors ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2013-06-01
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BJ20130098
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