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1. Comparative efficacy of ofatumumab versus oral therapies for relapsing multiple sclerosis patients using propensity score analyses and simulated treatment comparisons.

Author

Riley, Nicholas, Drudge, Christopher, Nelson, Morag, Haltner, Anja, Barnett, Michael, Broadley, Simon, Butzkueven, Helmut, McCombe, Pamela, Van der Walt, Anneke, Wong, Erin O. Y., Merschhemke, Martin, Adlard, Nicholas, Walker, Rob, and Samjoo, Imtiaz A.

Subjects
MULTIPLE sclerosis treatment, MONOCLONAL antibodies, FINGOLIMOD, DISEASE progression, CLINICAL trials
Abstract

Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Manipulation of the host cell response to infection with Toxoplasma gondii

Author

Nelson, Morag M.

Subjects
616.960795
Abstract

The principal aim of the work presented in this thesis was to investigate the host-pathogen interaction in Toxoplasma gondii infected cells and to elucidate which proteins and pathways were involved in the host response to infection. Toxoplasma gondii is of clinical importance for both human and veterinary disease. There are currently no drugs available to treat the chronic stage of disease. The transcriptional response of host cells to Toxoplasma infection has previously been investigated using microarrays. Proteins are the functional molecules in the cell and the protein expression response is likely to differ from the transcriptional response due to gene expression control and post translational modifications. The advantage of a global proteomic expression profiling study of Toxoplasma gondii infected cells is that, in principle, all possible host responses could be identified without pre-supposing a specific mechanism. Advanced proteomic methods were developed and used to investigate the host protein response to infection with Toxoplasma gondii. A conventional gel-to-gel approach was used in concert with difference gel electrophoresis (DIGE) to investigate the protein expression in infected cells. This part of the work concluded that the patterns of protein expression in infected cells showed clear differences from that of the non-infected cell. This resulted in the unambiguous identification of one hundred and fifty seven host proteins which changed in expression during infection with Toxoplasma gondii. Many proteins not previously implicated in response to infection were identified. The results from the proteomic studies were compared with the transcriptional study in order to determine the gene to protein correlation in Toxoplasma gondii infected cells. A weakly positive correlation between gene and protein expression was determined. To investigate whether the host response is uniquely tailored to an individual pathogen or whether cells have a common response to infection, the protein response to a second intracellular parasite, Leishmania major, was investigated. Far fewer changes were seen in the L.major infected cell proteome, proving that the host response to infection is unique to the pathogen. Phosphorylation is one the most common post translational modifications therefore the host cell phosphoproteome was investigated alongside the steady state proteome of infected cells using three techniques and proteins specifically phosphorylated due to the presence of the parasite were identified. Functional analysis of the modulated proteins revealed extensive modulation of many pathways and functions within the infected host cell including glycolytic, mitotic and structural proteins. Over one third of all the modulated proteins identified were mitochondrial. Overall the findings detailed in this thesis indicate that the host cell has a highly specific response to Toxoplasma gondii infection and that many host cell functions are modulated due to the presence of the parasite and reveal the intimate molecular relationship between host and parasite.

Published
2006
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3. 241 - Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: Results from a randomized, double-blind, placebo-controlled phase 2 trial.

Author

Nelson, Morag, Sanyal, Arun J, Bedossa, Pierre, Fraessdorf, Mandy, Neff, Guy W, Lawitz, Eric, Bugianesi, Elisabetta, Anstee, Quentin M, Hussain, Samina Ajaz, Newsome, Philip N, Ratziu, Vlad, Hosseini-Tabatabaei, Azadeh, Schattenberg, Joern M, Noureddin, Mazen, Alkhouri, Naim, and Younes, Ramy

Published
2024
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4. Identification of phosphorylated proteins in erythrocytes infected by the human malaria parasite Plasmodium falciparum

Author

Xia Dong, Quaile Andrew, Nelson Morag M, Wu Yang, Wastling Jonathan M, and Craig Alister

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Previous comparative proteomic analysis on Plasmodium falciparum isolates of different adhesion properties suggested that protein phosphorylation varies between isolates with different cytoadherence properties. But the extent and dynamic changes in phosphorylation have not been systematically studied. As a baseline for these future studies, this paper examined changes in the phosphoproteome of parasitized red blood cells (pRBC). Methods Metabolic labelling with [35S] methionine on pRBC and 2D gel electrophoresis (2-DE) has previously been used to show the expression of parasite proteins and changes in protein iso-electric point (PI). 2-DE of different parasite strains was combined with immunoblotting using monoclonal antibodies specifically to phosphorylated serine/threonine and tyrosine, to obtain the phosphorylation profiles throughout the erythrocytic lifecycle. Affinity chromatography was used to purify/enrich phosphorylated proteins and these proteins from mature trophozoite stages which were identified using high-accuracy mass spectrometry and MASCOT search. Results 2D-immunoblots showed that P. falciparum infection greatly increased phosphorylation of a set of proteins in pRBC, the dominant size classes for phosphorylated tyrosine proteins were 95, 60, 50 and 30 kDa and for phosphorylated serine/threonine were 120, 95, 60, 50, 43, 40 and 30 kDa. The most abundant molecules from 2D-gel mapping of phosphorylated proteins in ItG infected RBCs were identified by MALDI-TOF. A proteomic overview of phosphorylated proteins in pRBC was achieved by using complementary phosphorylated protein enrichment techniques combined with nano-flow LC/MS/MS analysis and MASCOT MS/MS ions search with phosphorylation as variable modifications. The definite phosphoproteins of pRBC are reported and discussed. Conclusion Protein phosphorylation is a major process in P. falciparum-parasitized erythrocytes. Preliminary screens identified 170 P. falciparum proteins and 77 human proteins as phosphorylated protein in pRBC, while only 48 human proteins were identified in the corresponding fractions from uninfected RBC. Refinement of the search to include significant ion scores indicating a specific phospho-peptide identified 21 P. falciparum proteins and 14 human proteins from pRBC, 13 host proteins were identified from normal RBC. The results achieved by complementary techniques consistently reflect a reliable proteomic overview of pRBC.

Published
2009
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5. Manipulation of the host cell response to infection with Toxoplasma gondii

Author

Nelson, Morag M

Subjects
Toxoplasma gondii, host-parasite relationships, parasitic diseases
Abstract

The principal aim of the work presented in this thesis was to investigate the host-pathogen interaction in Toxoplasma gondii infected cells and to elucidate which proteins and pathways were involved in the host response to infection. Toxoplasma gondii is of clinical importance for both human and veterinary disease. There are currently no drugs available to treat the chronic stage of disease. The transcriptional response of host cells to Toxoplasma infection has previously been investigated using microarrays. Proteins are the functional molecules in the cell and the protein expression response is likely to differ from the transcriptional response due to gene expression control and post translational modifications. The advantage of a global proteomic expression profiling study of Toxoplasma gondii infected cells is that, in principle, all possible host responses could be identified without pre-supposing a specific mechanism. Advanced proteomic methods were developed and used to investigate the host protein response to infection with Toxoplasma gondii. A conventional gel-to-gel approach was used in concert with difference gel electrophoresis (DIGE) to investigate the protein expression in infected cells. This part of the work concluded that the patterns of protein expression in infected cells showed clear differences from that of the non-infected cell. This resulted in the unambiguous identification of one hundred and fifty seven host proteins which changed in expression during infection with Toxoplasma gondii. Many proteins not previously implicated in response to infection were identified. The results from the proteomic studies were compared with the transcriptional study in order to determine the gene to protein correlation in Toxoplasma gondii infected cells. A weakly positive correlation between gene and protein expression was determined. To investigate whether the host response is uniquely tailored to an individual pathogen or whether cells have a common response to infection, the protein response to a second intracellular parasite, Leishmania major, was investigated. Far fewer changes were seen in the L.major infected cell proteome, proving that the host response to infection is unique to the pathogen. Phosphorylation is one the most common post translational modifications therefore the host cell phosphoproteome was investigated alongside the steady state proteome of infected cells using three techniques and proteins specifically phosphorylated due to the presence of the parasite were identified. Functional analysis of the modulated proteins revealed extensive modulation of many pathways and functions within the infected host cell including glycolytic, mitotic and structural proteins. Over one third of all the modulated proteins identified were mitochondrial. Overall the findings detailed in this thesis indicate that the host cell has a highly specific response to Toxoplasma gondii infection and that many host cell functions are modulated due to the presence of the parasite and reveal the intimate molecular relationship between host and parasite.

Published
2006
Full Text
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7. Identification of phosphorylated proteins in erythrocytes infected by the human malaria parasite Plasmodium falciparum.

Author

Yang Wu, Nelson, Morag M., Quaile, Andrew, Dong Xia, Wastling, Jonathan M., and Craig, Alister

Subjects
*COMPARATIVE studies, *ERYTHROCYTES, *PLASMODIUM, *PLASMODIUM falciparum, *MALARIA, *MOLECULAR biology
Abstract

Background: Previous comparative proteomic analysis on Plasmodium falciparum isolates of different adhesion properties suggested that protein phosphorylation varies between isolates with different cytoadherence properties. But the extent and dynamic changes in phosphorylation have not been systematically studied. As a baseline for these future studies, this paper examined changes in the phosphoproteome of parasitized red blood cells (pRBC). Methods: Metabolic labelling with [35S] methionine on pRBC and 2D gel electrophoresis (2-DE) has previously been used to show the expression of parasite proteins and changes in protein iso-electric point (PI). 2-DE of different parasite strains was combined with immunoblotting using monoclonal antibodies specifically to phosphorylated serine/threonine and tyrosine, to obtain the phosphorylation profiles throughout the erythrocytic lifecycle. Affinity chromatography was used to purify/enrich phosphorylated proteins and these proteins from mature trophozoite stages which were identified using high-accuracy mass spectrometry and MASCOT search. Results: 2D-immunoblots showed that P. falciparum infection greatly increased phosphorylation of a set of proteins in pRBC, the dominant size classes for phosphorylated tyrosine proteins were 95, 60, 50 and 30 kDa and for phosphorylated serine/threonine were 120, 95, 60, 50, 43, 40 and 30 kDa. The most abundant molecules from 2D-gel mapping of phosphorylated proteins in ItG infected RBCs were identified by MALDI-TOF. A proteomic overview of phosphorylated proteins in pRBC was achieved by using complementary phosphorylated protein enrichment techniques combined with nano-flow LC/MS/MS analysis and MASCOT MS/MS ions search with phosphorylation as variable modifications. The definite phosphoproteins of pRBC are reported and discussed. Conclusion: Protein phosphorylation is a major process in P. falciparum-parasitized erythrocytes. Preliminary screens identified 170 P. falciparum proteins and 77 human proteins as phosphorylated protein in pRBC, while only 48 human proteins were identified in the corresponding fractions from uninfected RBC. Refinement of the search to include significant ion scores indicating a specific phospho-peptide identified 21 P. falciparum proteins and 14 human proteins from pRBC, 13 host proteins were identified from normal RBC. The results achieved by complementary techniques consistently reflect a reliable proteomic overview of pRBC. [ABSTRACT FROM AUTHOR]

Published
2009
Full Text
View/download PDF

8. Manipulation of the host cell response to infection with Toxoplasma gondii

Author

Nelson, Morag M. and Nelson, Morag M.

Abstract

The principal aim of the work presented in this thesis was to investigate the host-pathogen interaction in Toxoplasma gondii infected cells and to elucidate which proteins and pathways were involved in the host response to infection. Toxoplasma gondii is of clinical importance for both human and veterinary disease. There are currently no drugs available to treat the chronic stage of disease. The transcriptional response of host cells to Toxoplasma infection has previously been investigated using microarrays. Proteins are the functional molecules in the cell and the protein expression response is likely to differ from the transcriptional response due to gene expression control and post translational modifications. The advantage of a global proteomic expression profiling study of Toxoplasma gondii infected cells is that, in principle, all possible host responses could be identified without pre-supposing a specific mechanism. Advanced proteomic methods were developed and used to investigate the host protein response to infection with Toxoplasma gondii. A conventional gel-to-gel approach was used in concert with difference gel electrophoresis (DIGE) to investigate the protein expression in infected cells. This part of the work concluded that the patterns of protein expression in infected cells showed clear differences from that of the non-infected cell. This resulted in the unambiguous identification of one hundred and fifty seven host proteins which changed in expression during infection with Toxoplasma gondii. Many proteins not previously implicated in response to infection were identified. The results from the proteomic studies were compared with the transcriptional study in order to determine the gene to protein correlation in Toxoplasma gondii infected cells. A weakly positive correlation between gene and protein expression was determined. To investigate whether the host response is uniquely tailored to an individual pathogen or whether cells have a common response

9. Manipulation of the host cell response to infection with Toxoplasma gondii

Author

Nelson, Morag M. and Nelson, Morag M.

Abstract

The principal aim of the work presented in this thesis was to investigate the host-pathogen interaction in Toxoplasma gondii infected cells and to elucidate which proteins and pathways were involved in the host response to infection. Toxoplasma gondii is of clinical importance for both human and veterinary disease. There are currently no drugs available to treat the chronic stage of disease. The transcriptional response of host cells to Toxoplasma infection has previously been investigated using microarrays. Proteins are the functional molecules in the cell and the protein expression response is likely to differ from the transcriptional response due to gene expression control and post translational modifications. The advantage of a global proteomic expression profiling study of Toxoplasma gondii infected cells is that, in principle, all possible host responses could be identified without pre-supposing a specific mechanism. Advanced proteomic methods were developed and used to investigate the host protein response to infection with Toxoplasma gondii. A conventional gel-to-gel approach was used in concert with difference gel electrophoresis (DIGE) to investigate the protein expression in infected cells. This part of the work concluded that the patterns of protein expression in infected cells showed clear differences from that of the non-infected cell. This resulted in the unambiguous identification of one hundred and fifty seven host proteins which changed in expression during infection with Toxoplasma gondii. Many proteins not previously implicated in response to infection were identified. The results from the proteomic studies were compared with the transcriptional study in order to determine the gene to protein correlation in Toxoplasma gondii infected cells. A weakly positive correlation between gene and protein expression was determined. To investigate whether the host response is uniquely tailored to an individual pathogen or whether cells have a common response

10. Manipulation of the host cell response to infection with Toxoplasma gondii

Author

Nelson, Morag M. and Nelson, Morag M.

Abstract

The principal aim of the work presented in this thesis was to investigate the host-pathogen interaction in Toxoplasma gondii infected cells and to elucidate which proteins and pathways were involved in the host response to infection. Toxoplasma gondii is of clinical importance for both human and veterinary disease. There are currently no drugs available to treat the chronic stage of disease. The transcriptional response of host cells to Toxoplasma infection has previously been investigated using microarrays. Proteins are the functional molecules in the cell and the protein expression response is likely to differ from the transcriptional response due to gene expression control and post translational modifications. The advantage of a global proteomic expression profiling study of Toxoplasma gondii infected cells is that, in principle, all possible host responses could be identified without pre-supposing a specific mechanism. Advanced proteomic methods were developed and used to investigate the host protein response to infection with Toxoplasma gondii. A conventional gel-to-gel approach was used in concert with difference gel electrophoresis (DIGE) to investigate the protein expression in infected cells. This part of the work concluded that the patterns of protein expression in infected cells showed clear differences from that of the non-infected cell. This resulted in the unambiguous identification of one hundred and fifty seven host proteins which changed in expression during infection with Toxoplasma gondii. Many proteins not previously implicated in response to infection were identified. The results from the proteomic studies were compared with the transcriptional study in order to determine the gene to protein correlation in Toxoplasma gondii infected cells. A weakly positive correlation between gene and protein expression was determined. To investigate whether the host response is uniquely tailored to an individual pathogen or whether cells have a common response

11. Manipulation of the host cell response to infection with Toxoplasma gondii

Author

Nelson, Morag M. and Nelson, Morag M.

Abstract

The principal aim of the work presented in this thesis was to investigate the host-pathogen interaction in Toxoplasma gondii infected cells and to elucidate which proteins and pathways were involved in the host response to infection. Toxoplasma gondii is of clinical importance for both human and veterinary disease. There are currently no drugs available to treat the chronic stage of disease. The transcriptional response of host cells to Toxoplasma infection has previously been investigated using microarrays. Proteins are the functional molecules in the cell and the protein expression response is likely to differ from the transcriptional response due to gene expression control and post translational modifications. The advantage of a global proteomic expression profiling study of Toxoplasma gondii infected cells is that, in principle, all possible host responses could be identified without pre-supposing a specific mechanism. Advanced proteomic methods were developed and used to investigate the host protein response to infection with Toxoplasma gondii. A conventional gel-to-gel approach was used in concert with difference gel electrophoresis (DIGE) to investigate the protein expression in infected cells. This part of the work concluded that the patterns of protein expression in infected cells showed clear differences from that of the non-infected cell. This resulted in the unambiguous identification of one hundred and fifty seven host proteins which changed in expression during infection with Toxoplasma gondii. Many proteins not previously implicated in response to infection were identified. The results from the proteomic studies were compared with the transcriptional study in order to determine the gene to protein correlation in Toxoplasma gondii infected cells. A weakly positive correlation between gene and protein expression was determined. To investigate whether the host response is uniquely tailored to an individual pathogen or whether cells have a common response

12. Manipulation of the host cell response to infection with Toxoplasma gondii

Author

Nelson, Morag M. and Nelson, Morag M.

Abstract

The principal aim of the work presented in this thesis was to investigate the host-pathogen interaction in Toxoplasma gondii infected cells and to elucidate which proteins and pathways were involved in the host response to infection. Toxoplasma gondii is of clinical importance for both human and veterinary disease. There are currently no drugs available to treat the chronic stage of disease. The transcriptional response of host cells to Toxoplasma infection has previously been investigated using microarrays. Proteins are the functional molecules in the cell and the protein expression response is likely to differ from the transcriptional response due to gene expression control and post translational modifications. The advantage of a global proteomic expression profiling study of Toxoplasma gondii infected cells is that, in principle, all possible host responses could be identified without pre-supposing a specific mechanism. Advanced proteomic methods were developed and used to investigate the host protein response to infection with Toxoplasma gondii. A conventional gel-to-gel approach was used in concert with difference gel electrophoresis (DIGE) to investigate the protein expression in infected cells. This part of the work concluded that the patterns of protein expression in infected cells showed clear differences from that of the non-infected cell. This resulted in the unambiguous identification of one hundred and fifty seven host proteins which changed in expression during infection with Toxoplasma gondii. Many proteins not previously implicated in response to infection were identified. The results from the proteomic studies were compared with the transcriptional study in order to determine the gene to protein correlation in Toxoplasma gondii infected cells. A weakly positive correlation between gene and protein expression was determined. To investigate whether the host response is uniquely tailored to an individual pathogen or whether cells have a common response

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