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Article ; Online: Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease.

D'Alessandro, Angelo / Le, Kang / Lundt, Maureen / Li, Quan / Dunkelberger, Emily B / Cellmer, Troy / Worth, Andrew J / Patil, Spurthi / Huston, Chris / Grier, Abby / Dzieciatkowska, Monika / Stephenson, Daniel / Eaton, William A / Thein, Swee Lay

Haematologica

2024

Abstract: Mitapivat, a pyruvate kinase (PK) activator, shows great potential as a sickle cell disease (SCD)- modifying therapy. Safety and efficacy of mitapivat as a long-term maintenance therapy is currently being evaluated in two open-label studies. Here we ... ...

Abstract	Mitapivat, a pyruvate kinase (PK) activator, shows great potential as a sickle cell disease (SCD)- modifying therapy. Safety and efficacy of mitapivat as a long-term maintenance therapy is currently being evaluated in two open-label studies. Here we apply a comprehensive multi-omics approach to investigate the impact of activating PK on red blood cells (RBCs) from 15 SCD patients. HbSS patients were enrolled in one of the open label, extended studies (NCT04610866). Leuko-depleted RBCs obtained from fresh whole blood at baseline (visit 1, V1), prior to drug initiation and longitudinal time points over the course of the study were processed for multiomics through a stepwise extraction of metabolites, lipids and proteins. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBCs. Mitapivat decreased 2,3-diphosphoglycerate (DPG) levels, increased adenosine triphosphate (ATP) levels, and improved hematologic and sickling parameters in patients with SCD. Agreement between omics measurements and clinical measurements confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of hemoglobin S (HbS) oxygen affinity (p50) and sickling kinetics (t50) during treatment. Mitapivat markedly reduced levels of proteins of mitochondrial origin within 2 weeks of initiation of drug treatment, with minimal changes in the reticulocyte counts. The first six months of treatment also witnessed transient elevation of lysophosphatidylcholines and oxylipins with depletion in free fatty acids, suggestive of an effect on membrane lipid remodeling. Multi-omics analysis of RBCs identified benefits for glycolysis, as well as activation of the Lands cycle.
Language	English
Publishing date	2024-03-07
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.284831
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Article ; Online: Classification performance of administrative coding data for detection of invasive fungal infection in paediatric cancer patients.

Valentine, Jake C / Worth, Leon J / Verspoor, Karin M / Hall, Lisa / Yeoh, Daniel K / Thursky, Karin A / Clark, Julia E / Haeusler, Gabrielle M

PloS one

2020 Volume 15, Issue 9, Page(s) e0238889

Abstract: Background: Invasive fungal infection (IFI) detection requires application of complex case definitions by trained staff. Administrative coding data (ICD-10-AM) may provide a simplified method for IFI surveillance, but accuracy of case ascertainment in ... ...

Abstract	Background: Invasive fungal infection (IFI) detection requires application of complex case definitions by trained staff. Administrative coding data (ICD-10-AM) may provide a simplified method for IFI surveillance, but accuracy of case ascertainment in children with cancer is unknown. Objective: To determine the classification performance of ICD-10-AM codes for detecting IFI using a gold-standard dataset (r-TERIFIC) of confirmed IFIs in paediatric cancer patients at a quaternary referral centre (Royal Children's Hospital) in Victoria, Australia from 1st April 2004 to 31st December 2013. Methods: ICD-10-AM codes denoting IFI in paediatric patients (<18-years) with haematologic or solid tumour malignancies were extracted from the Victorian Admitted Episodes Dataset and linked to the r-TERIFIC dataset. Sensitivity, positive predictive value (PPV) and the F1 scores of the ICD-10-AM codes were calculated. Results: Of 1,671 evaluable patients, 113 (6.76%) had confirmed IFI diagnoses according to gold-standard criteria, while 114 (6.82%) cases were identified using the codes. Of the clinical IFI cases, 68 were in receipt of ≥1 ICD-10-AM code(s) for IFI, corresponding to an overall sensitivity, PPV and F1 score of 60%, respectively. Sensitivity was highest for proven IFI (77% [95% CI: 58-90]; F1 = 47%) and invasive candidiasis (83% [95% CI: 61-95]; F1 = 76%) and lowest for other/unspecified IFI (20% [95% CI: 5.05-72%]; F1 = 5.00%). The most frequent misclassification was coding of invasive aspergillosis as invasive candidiasis. Conclusion: ICD-10-AM codes demonstrate moderate sensitivity and PPV to detect IFI in children with cancer. However, specific subsets of proven IFI and invasive candidiasis (codes B37.x) are more accurately coded.
MeSH term(s)	Australia/epidemiology ; Child ; Child, Preschool ; Current Procedural Terminology ; Databases, Factual ; Female ; Humans ; Invasive Fungal Infections/epidemiology ; Male ; Medical Records ; Neoplasms/microbiology ; Retrospective Studies ; Tertiary Care Centers
Language	English
Publishing date	2020-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0238889
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Article ; Online: Advances in imaging cell-matrix adhesions.

Worth, Daniel C / Parsons, Maddy

Journal of cell science

2010 Volume 123, Issue Pt 21, Page(s) 3629–3638

Abstract: Adhesion is fundamental to the survival and function of many different cell types, and regulates basic events such as mitosis, cell survival and migration, in both embryonic and adult organisms. Cell-matrix adhesion also regulates the dynamic interplay ... ...

Abstract	Adhesion is fundamental to the survival and function of many different cell types, and regulates basic events such as mitosis, cell survival and migration, in both embryonic and adult organisms. Cell-matrix adhesion also regulates the dynamic interplay between cells and surrounding tissues during processes such as immune cell recruitment, wound healing and cancer cell metastasis. The study of cell adhesion has gained momentum in recent years, in large part because of the emergence of imaging techniques that have facilitated detailed analysis of the molecular composition and dynamics of the structures involved. In this Commentary, we discuss the recent application of different imaging techniques to study cell-matrix adhesions, emphasising common strategies used for the analysis of adhesion dynamics both in cells in culture and in whole organisms.
MeSH term(s)	Animals ; Cell Adhesion ; Fluorescence Resonance Energy Transfer ; Focal Adhesions/metabolism ; Humans ; Microscopy/methods ; Microscopy/trends
Language	English
Publishing date	2010-10-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.064485
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Article ; Online: Live cell imaging analysis of receptor function.

Worth, Daniel C / Parsons, Maddy

Methods in molecular biology (Clifton, N.J.)

2009 Volume 591, Page(s) 311–323

Abstract: Cell surface receptors are crucial in the regulation of a wide variety of signalling responses to extracellular stimuli such as soluble growth factors or matrix proteins. To respond effectively to rapidly changing environmental cues, many receptors are ... ...

Abstract	Cell surface receptors are crucial in the regulation of a wide variety of signalling responses to extracellular stimuli such as soluble growth factors or matrix proteins. To respond effectively to rapidly changing environmental cues, many receptors are rapidly endo- or exo-cytosed to either subcellular or membrane compartments or they recruit specific intracellular binding partners. Recent advances in microscopy techniques have made it possible to study receptor behaviour in live cells to gain a better understanding of dynamics, binding partners and sub-cellular localisation. Here we describe several common currently used techniques to study receptor behaviour in living cells.
MeSH term(s)	Cell Survival ; Fluorescence Resonance Energy Transfer ; Fluorescent Dyes/metabolism ; Humans ; Kinetics ; Microscopy, Confocal ; Molecular Imaging/methods ; Photobleaching ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Transport ; Receptors, Cell Surface/chemistry ; Receptors, Cell Surface/metabolism
Chemical Substances	Fluorescent Dyes ; Receptors, Cell Surface
Language	English
Publishing date	2009-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-60761-404-3_18
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Article: Advances in imaging cell-matrix adhesions

Worth, Daniel C / Parsons, Maddy

Journal of cell science. 2010 Nov. 1, v. 123, no. 21

2010

Abstract	Adhesion is fundamental to the survival and function of many different cell types, and regulates basic events such as mitosis, cell survival and migration, in both embryonic and adult organisms. Cell-matrix adhesion also regulates the dynamic interplay between cells and surrounding tissues during processes such as immune cell recruitment, wound healing and cancer cell metastasis. The study of cell adhesion has gained momentum in recent years, in large part because of the emergence of imaging techniques that have facilitated detailed analysis of the molecular composition and dynamics of the structures involved. In this Commentary, we discuss the recent application of different imaging techniques to study cell-matrix adhesions, emphasising common strategies used for the analysis of adhesion dynamics both in cells in culture and in whole organisms.
Language	English
Dates of publication	2010-1101
Size	p. 3629-3638.
Publishing place	The Company of Biologists Limited
Document type	Article
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Commentary on the impact of the COVID-19 pandemic on opioid use disorder treatment among Indigenous communities in the United States and Canada.

Wendt, Dennis C / Marsan, Stéphanie / Parker, Daniel / Lizzy, Karen E / Roper, Jessica / Mushquash, Christopher / Venner, Kamilla L / Lam, Alice / Swansburg, Jennifer / Worth, Nancy / Sorlagas, Nicholas / Quach, Tania / Manoukian, Kristapore / Bernett, Payton / Radin, Sandra M

Journal of substance abuse treatment

2020 Volume 121, Page(s) 108165

Abstract: This commentary focuses on how some Indigenous communities in the United States (U.S.) and Canada are addressing the opioid epidemic within the context of the COVID-19 pandemic, from the perspective of the co-authors as researchers, clinicians, and ... ...

Abstract	This commentary focuses on how some Indigenous communities in the United States (U.S.) and Canada are addressing the opioid epidemic within the context of the COVID-19 pandemic, from the perspective of the co-authors as researchers, clinicians, and pharmacists working within or among Indigenous communities in three eastern Canadian provinces and two western U.S. states. The pandemic has likely exacerbated opioid use problems among Indigenous communities, especially for individuals with acute distress or comorbid mental illness, or who are in need of withdrawal management or residential services. In response to the pandemic, we discuss first how greater prescription flexibility has facilitated and even increased access to medications for opioid use disorder. Second, we describe how Indigenous-serving clinics have expanded telemedicine services, albeit not without some challenges. Third, we note challenges with restricted participation in traditional Indigenous healing practices that can be helpful for addiction recovery. Fourth, we mention providers' worries about the pandemic's impact on their patients' mental health and safety. We argue that certain treatment transformations may be helpful even after the pandemic is over, through enhancing access to community-grounded treatment, decreasing stigma, and promoting patient self-efficacy.
MeSH term(s)	Buprenorphine/therapeutic use ; COVID-19 ; Canada ; Humans ; Indigenous Peoples ; Mental Health ; Narcotic Antagonists/therapeutic use ; Opiate Substitution Treatment ; Opioid-Related Disorders/rehabilitation ; Practice Patterns, Physicians' ; Telemedicine ; United States
Chemical Substances	Narcotic Antagonists ; Buprenorphine (40D3SCR4GZ)
Keywords	covid19
Language	English
Publishing date	2020-10-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	605923-5
ISSN	1873-6483 ; 0740-5472
ISSN (online)	1873-6483
ISSN	0740-5472
DOI	10.1016/j.jsat.2020.108165
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Article: Probabilistic modelling of developmental neurotoxicity based on a simplified adverse outcome pathway network.

Spînu, Nicoleta / Cronin, Mark T D / Lao, Junpeng / Bal-Price, Anna / Campia, Ivana / Enoch, Steven J / Madden, Judith C / Mora Lagares, Liadys / Novič, Marjana / Pamies, David / Scholz, Stefan / Villeneuve, Daniel L / Worth, Andrew P

Computational toxicology (Amsterdam, Netherlands)

2020 Volume 21, Page(s) 100206

Abstract: In a century where toxicology and chemical risk assessment are embracing alternative methods to animal testing, there is an opportunity to understand the causal factors of neurodevelopmental disorders such as learning and memory disabilities in children, ...

Abstract	In a century where toxicology and chemical risk assessment are embracing alternative methods to animal testing, there is an opportunity to understand the causal factors of neurodevelopmental disorders such as learning and memory disabilities in children, as a foundation to predict adverse effects. New testing paradigms, along with the advances in probabilistic modelling, can help with the formulation of mechanistically-driven hypotheses on how exposure to environmental chemicals could potentially lead to developmental neurotoxicity (DNT). This investigation aimed to develop a Bayesian hierarchical model of a simplified AOP network for DNT. The model predicted the probability that a compound induces each of three selected common key events (CKEs) of the simplified AOP network and the adverse outcome (AO) of DNT, taking into account correlations and causal relations informed by the key event relationships (KERs). A dataset of 88 compounds representing pharmaceuticals, industrial chemicals and pesticides was compiled including physicochemical properties as well as
Language	English
Publishing date	2020-09-21
Publishing country	Netherlands
Document type	Journal Article
ISSN	2468-1113
ISSN	2468-1113
DOI	10.1016/j.comtox.2021.100206
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Article: Adhesion dynamics: mechanisms and measurements.

Worth, Daniel C / Parsons, Maddy

The international journal of biochemistry & cell biology

2008 Volume 40, Issue 11, Page(s) 2397–2409

Abstract: Adhesion to the extracellular matrix (ECM) is a fundamental requirement for survival, differentiation and migration of numerous cell types during both embryonic development and adult homeostasis. Different types of adhesion structures have been ... ...

Abstract	Adhesion to the extracellular matrix (ECM) is a fundamental requirement for survival, differentiation and migration of numerous cell types during both embryonic development and adult homeostasis. Different types of adhesion structures have been classified in different cell types or tissue environments. The best studied of these are focal adhesions which are found on a wide variety of cell types and will be the main focus of this review. Many years of research into the control of adhesion has yielded a wealth of information regarding the complexity of protein composition of these critical points of cell:ECM contact. Moreover, it has emerged that adhesions are not only highly ordered, but also dynamic structures under tight spatial control at the subcellular level to enable localised responses to extracellular cues. However, it is only in the last decade that the relative dynamics of these adhesion proteins have been closely studied. Here we provide an overview of the imaging strategies that have been developed and implemented to study the intricacies and hierarchy of protein turnover within focal adhesions. The caveats of employing these imaging techniques, as well as future directions will also be discussed.
MeSH term(s)	Cell Adhesion/physiology ; Cell Adhesion Molecules/metabolism ; Extracellular Matrix/metabolism ; Fluorescence Recovery After Photobleaching ; Fluorescence Resonance Energy Transfer ; Focal Adhesions/chemistry ; Focal Adhesions/metabolism ; Imaging, Three-Dimensional ; Microscopy/methods
Chemical Substances	Cell Adhesion Molecules
Language	English
Publishing date	2008-04-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2008.04.008
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Article ; Online: Seminar: Extracellular Vesicles as Mediators of Environmental Stress in Human Disease.

Kalia, Vrinda / Baccarelli, Andrea A / Happel, Christine / Hollander, Jonathan A / Jukic, Anne Marie / McAllister, Kimberly A / Menon, Ramkumar / Merrick, Bruce A / Milosavljevic, Aleksander / Ravichandran, Lingamanaidu V / Roth, Matthew E / Subramanian, Anita / Tyson, Frederick L / Worth, Leroy / Shaughnessy, Daniel T

Environmental health perspectives

2023 Volume 131, Issue 10, Page(s) 104201

Abstract: Background: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular ... ...

Abstract	Background: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress. Objectives: This seminar addresses the application of new tools and approaches for EV research, developed in part through the National Institutes of Health (NIH) Extracellular RNA Communication Program, and reflects presentations and discussions from a workshop held 27-28 September 2021 by the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Advancing Translational Sciences (NCATS) on "Extracellular Vesicles, Exosomes, and Cell-Cell Signaling in Response to Environmental Stress." The panel of experts discussed current research on EVs and environmental exposures, highlighted recent advances in EV isolation and characterization, and considered research gaps and opportunities toward identifying and characterizing the roles for EVs in environmentally related diseases, as well as the current challenges and opportunities in this field. Discussion: The authors discuss the application of new experimental models, particularly organ-on-chip (OOC) systems and
MeSH term(s)	Humans ; Biomarkers/metabolism ; Environmental Exposure ; Exosomes/metabolism ; Extracellular Vesicles/metabolism ; RNA/metabolism
Chemical Substances	Biomarkers ; RNA (63231-63-0)
Language	English
Publishing date	2023-10-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/EHP12980
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Article ; Online: Greater Species Richness of Bacterial Skin Symbionts Better Suppresses the Amphibian Fungal Pathogen Batrachochytrium Dendrobatidis.

Piovia-Scott, Jonah / Rejmanek, Daniel / Woodhams, Douglas C / Worth, S Joy / Kenny, Heather / McKenzie, Valerie / Lawler, Sharon P / Foley, Janet E

Microbial ecology

2017 Volume 74, Issue 1, Page(s) 217–226

Abstract: The symbiotic microbes that grow in and on many organisms can play important roles in protecting their hosts from pathogen infection. While species diversity has been shown to influence community function in many other natural systems, the question of ... ...

Abstract	The symbiotic microbes that grow in and on many organisms can play important roles in protecting their hosts from pathogen infection. While species diversity has been shown to influence community function in many other natural systems, the question of how species diversity of host-associated symbiotic microbes contributes to pathogen resistance is just beginning to be explored. Understanding diversity effects on pathogen resistance could be particularly helpful in combating the fungal pathogen Batrachochytrium dendrobatidis (Bd) which has caused dramatic population declines in many amphibian species and is a major concern for amphibian conservation. Our study investigates the ability of host-associated bacteria to inhibit the proliferation of Bd when grown in experimentally assembled biofilm communities that differ in species number and composition. Six bacterial species isolated from the skin of Cascades frogs (Rana cascadae) were used to assemble bacterial biofilm communities containing 1, 2, 3, or all 6 bacterial species. Biofilm communities were grown with Bd for 7 days following inoculation. More speciose bacterial communities reduced Bd abundance more effectively. This relationship between bacterial species richness and Bd suppression appeared to be driven by dominance effects-the bacterial species that were most effective at inhibiting Bd dominated multi-species communities-and complementarity: multi-species communities inhibited Bd growth more than monocultures of constituent species. These results underscore the notion that pathogen resistance is an emergent property of microbial communities, a consideration that should be taken into account when designing probiotic treatments to reduce the impacts of infectious disease.
MeSH term(s)	Animals ; Antibiosis ; Bacteria ; Chytridiomycota/pathogenicity ; Ranidae/microbiology ; Skin/microbiology ; Symbiosis
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	1462065-0
ISSN	1432-184X ; 0095-3628
ISSN (online)	1432-184X
ISSN	0095-3628
DOI	10.1007/s00248-016-0916-4
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