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Article ; Online: Development and Validation of a Flexible Sensing Array for Placement within the Physical Human-Exoskeleton Interface.

Turnbull, Rory Peter / Evans, Elaine / Dehghani-Sanij, Abbas Ali

IEEE ... International Conference on Rehabilitation Robotics : [proceedings

2023 Volume 2023, Page(s) 1–6

Abstract: Monitoring the human-exoskeleton interface (HEI) is vital for user safety in assistive exoskeletons. Considering interaction forces during design can improve comfort and efficiency and reduce resistance and inertia. Challenges include covering the lower ... ...

Abstract	Monitoring the human-exoskeleton interface (HEI) is vital for user safety in assistive exoskeletons. Considering interaction forces during design can improve comfort and efficiency and reduce resistance and inertia. Challenges include covering the lower limb area without interfering with user-robot interaction. This paper presents a force-sensitive resistor (FSR) based sensing sleeve for use within the HEI. The design includes 30 sensors and works independently of it to assess attachment modalities. System characterisation tests the system with human trials. Demonstrating that a low-cost, flexible sensing array can accurately monitor HEI. This provides a promising tool for assessing human-robot interaction and investigating wearable robotic device use.
MeSH term(s)	Humans ; Exoskeleton Device ; Robotics ; Lower Extremity ; Physical Examination ; Mechanical Phenomena
Language	English
Publishing date	2023-11-09
Publishing country	United States
Document type	Journal Article
ISSN	1945-7901
ISSN (online)	1945-7901
DOI	10.1109/ICORR58425.2023.10304686
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Harnessing the Nucleolar DNA Damage Response in Cancer Therapy.

Xuan, Jiachen / Gitareja, Kezia / Brajanovski, Natalie / Sanij, Elaine

Genes

2021 Volume 12, Issue 8

Abstract: The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. They serve as the site of rRNA synthesis and processing, and ribosome assembly. There are 400-600 copies of rRNA genes (rDNA) in human cells and ... ...

Abstract	The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. They serve as the site of rRNA synthesis and processing, and ribosome assembly. There are 400-600 copies of rRNA genes (rDNA) in human cells and their highly repetitive and transcribed nature poses a challenge for DNA repair and replication machineries. It is only in the last 7 years that the DNA damage response and processes of DNA repair at the rDNA repeats have been recognized to be unique and distinct from the classic response to DNA damage in the nucleoplasm. In the last decade, the nucleolus has also emerged as a central hub for coordinating responses to stress via sequestering tumor suppressors, DNA repair and cell cycle factors until they are required for their functional role in the nucleoplasm. In this review, we focus on features of the rDNA repeats that make them highly vulnerable to DNA damage and the mechanisms by which rDNA damage is repaired. We highlight the molecular consequences of rDNA damage including activation of the nucleolar DNA damage response, which is emerging as a unique response that can be exploited in anti-cancer therapy. In this review, we focus on CX-5461, a novel inhibitor of Pol I transcription that induces the nucleolar DNA damage response and is showing increasing promise in clinical investigations.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Nucleolus/drug effects ; DNA Damage ; DNA, Ribosomal/genetics ; Humans ; Neoplasms/therapy
Chemical Substances	Antineoplastic Agents ; DNA, Ribosomal
Language	English
Publishing date	2021-07-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12081156
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Article: CX-5461 can destabilize replication forks in PARP inhibitor-resistant models of ovarian cancer.

Xuan, Jiachen / Pearson, Richard B / Sanij, Elaine

Molecular & cellular oncology

2020 Volume 7, Issue 6, Page(s) 1805256

Abstract: Acquired drug resistance leads to poor clinical outcome in high grade serous ovarian cancer (HGSOC). We have demonstrated the efficacy of the novel drug CX-5461 in HGSOC is mediated through destabilization of DNA replication forks. The data highlights ... ...

Abstract	Acquired drug resistance leads to poor clinical outcome in high grade serous ovarian cancer (HGSOC). We have demonstrated the efficacy of the novel drug CX-5461 in HGSOC is mediated through destabilization of DNA replication forks. The data highlights the potential of CX-5461 in overcoming a general mechanism of chemotherapeutic resistance.
Language	English
Publishing date	2020-08-31
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2020.1805256
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Article: Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer.

Inderjeeth, Andrisha-Jade / Topp, Monique / Sanij, Elaine / Castro, Elena / Sandhu, Shahneen

Cancers

2022 Volume 14, Issue 23

Abstract: Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging ... ...

Abstract	Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with
Language	English
Publishing date	2022-11-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14235922
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Article ; Online: ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia.

Behrens, Kira / Brajanovski, Natalie / Xu, Zhen / Viney, Elizabeth M / DiRago, Ladina / Hediyeh-Zadeh, Soroor / Davis, Melissa J / Pearson, Richard B / Sanij, Elaine / Alexander, Warren S / Ng, Ashley P

Science advances

2024 Volume 10, Issue 10, Page(s) eadj8803

Abstract: Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by ... ...

Abstract	Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the
MeSH term(s)	Animals ; Humans ; Mice ; Fusion Proteins, bcr-abl/genetics ; Fusion Proteins, bcr-abl/metabolism ; Fusion Proteins, bcr-abl/therapeutic use ; Gene Regulatory Networks ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Transcription Factors/genetics ; Transcriptional Regulator ERG/genetics
Chemical Substances	ERG protein, human ; Fusion Proteins, bcr-abl (EC 2.7.10.2) ; Transcription Factors ; Transcriptional Regulator ERG ; MYC protein, human
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adj8803
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Article ; Online: Persistence of

Harrop, Sean / Nguyen, Phillip C / Byrne, David / Wilson, Clarissa / Ryland, Georgina L / Nguyen, Tamia / Anderson, Mary Ann / Khaw, Seong Lin / Martin, Michelle / Tiong, Ing Soo / Sanij, Elaine / Blombery, Piers

EJHaem

2023 Volume 4, Issue 4, Page(s) 1105–1109

Abstract: ... ...

Abstract	UBTF
Language	English
Publishing date	2023-10-19
Publishing country	United States
Document type	Journal Article
ISSN	2688-6146
ISSN (online)	2688-6146
DOI	10.1002/jha2.808
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Article: Harnessing the Nucleolar DNA Damage Response in Cancer Therapy

Xuan, Jiachen / Gitareja, Kezia / Brajanovski, Natalie / Sanij, Elaine

Genes. 2021 July 28, v. 12, no. 8

2021

Abstract: The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. They serve as the site of rRNA synthesis and processing, and ribosome assembly. There are 400–600 copies of rRNA genes (rDNA) in human cells and ... ...

Abstract	The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. They serve as the site of rRNA synthesis and processing, and ribosome assembly. There are 400–600 copies of rRNA genes (rDNA) in human cells and their highly repetitive and transcribed nature poses a challenge for DNA repair and replication machineries. It is only in the last 7 years that the DNA damage response and processes of DNA repair at the rDNA repeats have been recognized to be unique and distinct from the classic response to DNA damage in the nucleoplasm. In the last decade, the nucleolus has also emerged as a central hub for coordinating responses to stress via sequestering tumor suppressors, DNA repair and cell cycle factors until they are required for their functional role in the nucleoplasm. In this review, we focus on features of the rDNA repeats that make them highly vulnerable to DNA damage and the mechanisms by which rDNA damage is repaired. We highlight the molecular consequences of rDNA damage including activation of the nucleolar DNA damage response, which is emerging as a unique response that can be exploited in anti-cancer therapy. In this review, we focus on CX-5461, a novel inhibitor of Pol I transcription that induces the nucleolar DNA damage response and is showing increasing promise in clinical investigations.
Keywords	DNA damage ; DNA repair ; cancer therapy ; cell cycle ; cell nucleolus ; humans ; neoplasms ; ribosomal RNA ; ribosomes
Language	English
Dates of publication	2021-0728
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12081156
Database	NAL-Catalogue (AGRICOLA)

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Article: Targeting the ribosome to treat multiple myeloma.

Maclachlan, Kylee H / Gitareja, Kezia / Kang, Jian / Cuddihy, Andrew / Cao, Yuxi / Hein, Nadine / Cullinane, Carleen / Ang, Ching-Seng / Brajanovski, Natalie / Pearson, Richard B / Khot, Amit / Sanij, Elaine / Hannan, Ross D / Poortinga, Gretchen / Harrison, Simon J

Molecular therapy. Oncology

2024 Volume 32, Issue 1, Page(s) 200771

Abstract: The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has ... ...

Abstract	The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article
ISSN	2950-3299
ISSN	2950-3299
DOI	10.1016/j.omton.2024.200771
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Article ; Online: Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy.

Kang, Jian / Brajanovski, Natalie / Chan, Keefe T / Xuan, Jiachen / Pearson, Richard B / Sanij, Elaine

Signal transduction and targeted therapy

2021 Volume 6, Issue 1, Page(s) 323

Abstract: Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In addition ... ...

Abstract	Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In addition to their canonical ribosomal functions, multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress, resulting in cell cycle arrest and apoptosis. Defects in ribosome biogenesis, translation, and the functions of individual RPs, including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies. Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life. Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer. In this article, we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer. We particularly discuss the molecular basis of the transition from hypo- to hyper-proliferation in ribosomopathies with elevated cancer risk, a paradox termed "Dameshek's riddle." Furthermore, we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects. We also highlight recent advances in ribosome stress-based cancer therapeutics. Importantly, insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.
MeSH term(s)	Cell Cycle Checkpoints/genetics ; Cell Proliferation/genetics ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/therapy ; Humans ; Molecular Targeted Therapy ; Mutation/genetics ; Neoplasms/genetics ; Neoplasms/therapy ; Ribosomal Proteins/genetics ; Ribosomal Proteins/therapeutic use ; Ribosomes/genetics
Chemical Substances	Ribosomal Proteins
Language	English
Publishing date	2021-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2886872-9
ISSN	2059-3635 ; 2095-9907
ISSN (online)	2059-3635
ISSN	2095-9907
DOI	10.1038/s41392-021-00728-8
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Article ; Online: Ribosomal proteins and human diseases

Jian Kang / Natalie Brajanovski / Keefe T. Chan / Jiachen Xuan / Richard B. Pearson / Elaine Sanij

Signal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-

molecular mechanisms and targeted therapy

2021 Volume 22

Abstract: Abstract Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In ... ...

Abstract	Abstract Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In addition to their canonical ribosomal functions, multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress, resulting in cell cycle arrest and apoptosis. Defects in ribosome biogenesis, translation, and the functions of individual RPs, including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies. Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life. Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer. In this article, we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer. We particularly discuss the molecular basis of the transition from hypo- to hyper-proliferation in ribosomopathies with elevated cancer risk, a paradox termed “Dameshek’s riddle.” Furthermore, we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects. We also highlight recent advances in ribosome stress-based cancer therapeutics. Importantly, insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.
Keywords	Medicine ; R ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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