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1. Modeling the human Nav1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Author

Ahmed M, Jalily Hasani H, Ganesan A, Houghton M, and Barakat K

Subjects
Sodium ion channel, voltage gated sodium channel, steered molecular dynamics, cardiotoxicity, hNav1.5, channel blockers., Therapeutics. Pharmacology, RM1-950
Abstract

Marawan Ahmed,1 Horia Jalily Hasani,1,* Aravindhan Ganesan,1,* Michael Houghton,2–4 Khaled Barakat1–3 1Faculty of Pharmacy and Pharmaceutical Sciences, 2Li Ka Shing Institute of Virology, 3Li Ka Shing Applied Virology Institute, 4Department of Medical Microbiology and Immunology, Katz Centre for Health Research, University of Alberta, Edmonton, AB, Canada *These authors contributed equally to this work Abstract: Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel’s selectivity filters to reach the channel’s central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed “state-of-the-art” steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure–property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel. Keywords: sodium ion channel, voltage-gated sodium channel, steered molecular dynamics, cardiotoxicity, hNav1.5, channel blockers

Published
2017

2. Gain in terahertz quantum cascade lasers

Author

Houghton, M.

Subjects
535
Abstract

This thesis focuses on experiments involving coupled cavity THz QCLs. These take the form of either monolithic devices with etched gaps to form two cavities on the same device, or separate devices aligned under vacuum and at cryogenic temperatures using a specially built piezo-electric micropositioner system. After an introductory chapter briefly reviewing the current state of QCL research, processing techniques and other standard experimental techniques, the thesis begins with the presentation of some experiments dealing with the effects of optical feedback between the two cavities. This leads on to a theoretical chapter in which a mathematical model of a double section QCL is presented, along with some explanation of some unexpected results seen experimentally. The final chapter returns to experimental work. Findings from the previous chapters are used to attempt to develop methods for the measurement of gain and loss in QCLs using coupled cavities, something for which there is currently no reliable method at THz frequencies and which involves considerable experimental difficulties. The thesis concludes with a discussion of possible future work including an extension of the mathematical model, and other possibilities to improve the gain measurement method.

Published
2008

5. Slow recovery of stream invertebrates on subantarctic Macquarie Island after eradication of introduced rabbits and regrowth of vegetation.

Author

Marchant, R., Kefford, B. J., Houghton, M., Wasley, J., and King, C. K.

Abstract

Context: Streams on subantarctic Macquarie Island were first sampled for freshwater invertebrates in 1992 when rabbit numbers were low. Then an average 11.6 taxa per site were recorded. Between 2000 and 2011, vegetation was overgrazed as rabbit numbers increased. In 2008 and 2010, 7.4–8.4 taxa per site were recorded, abundance of most taxa had decreased and greatest compositional changes occurred at sites exposed to moderate or severe vegetation damage. Rabbits were eradicated in 2011 and substantial regrowth of vegetation was evident by 2016. Aims: Sites were resampled in 2016 to determine the extent to which the invertebrate communities had changed after rabbit removal. Methods: In all, 13 of the original 15 sites sampled in 1992 were resampled. Five kick samples were taken at each site. Key results: Mean taxon richness (8.2 taxa per site) and community composition at individual sites remained, in 2016, very similar to that recorded in 2008 and 2010 when the island was heavily grazed. Conclusions: Recovery of stream invertebrate communities appeared to be slow, possibly because few refuges were available. Minor changes in climate and water quality did not influence recovery. Implications: Stream invertebrate communities could take a decade or more to recover. Species richness and community composition of stream invertebrates in 2016, after rabbits were eradicated from Macquarie Island in 2011, remain unchanged from what was observed in 2008 and 2010. Recovery and recolonisation appear slow, possibly because few refuges are available. Stream invertebrate communities could take a decade or more to recover. [ABSTRACT FROM AUTHOR]

Published
2023
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6. The CAESAR New Frontiers Mission: 1. Expected Nature of the Returned Comet Sample

Author

Lauretta, D. S, Squyres, S. W, Bermudez, L, Blake, G, Canham, J. S, Chu, P. C, Clemett, S, Dworkin, J. P, Furukawa, Y, Gerakines, P. A, Glavin, D. P, Herd, C. D. K, Houghton, M. B, Kimura, Y, Lorentson, C. C, Makowski, J. M, Messenger, S, Milam, S, Mumma, M, Nakamura-Messenger, K, Nakamura, T, Nguyen, A, Oberg, D, Pace, L. F, Spring, J. W, Takigawa, A, Violet, M, Zacny, K, and Zega, T. J

Subjects
Lunar And Planetary Science And Exploration
Abstract

Comets are time capsules from the birth of our Solar System that record pre-solar history, the initial stages of planet formation, and the sources of prebiotic organics and volatiles for the origin of life. These capsules can only be opened in laboratories on Earth. CAESAR (Comet Astrobiology Exploration Sample Return)’s sample analysis objectives are to understand the nature of Solar System starting materials and how these components came together to form planets and give rise to life. Examination of these comet nucleus surface samples in laboratories around the world will also provide ground truth to remote observations of the innumerable icy bodies of the Solar System.

Published
2019

7. The CAESAR New Frontiers Mission: Comet Surface Sample Acquisition and Preservation

Author

Glavin, D. P, Squyres, S. W, Chu, P. C, Gerakines, P. A, Yamada, K, Parker, J. E, Aslam, S, Clemett, S, Dworkin, J. P, Furukawa, Y, Gorevan, S, Gorius, N, Kolasinski, J, Hayes, A. G, Houghton, M. B, Lauretta, D. S, Messenger, S, Nakamura-Messenger, K, Peabody, H. L, Quilligan, G, Spring, J, Wegel, D. C, and Zacny, K. A

Subjects
Lunar And Planetary Science And Exploration
Abstract

NASA recently selected the Comet Astrobiology Exploration Sample Return (CAESAR) mission for Phase A study in the New Frontiers Program. This mission will acquire and return to Earth for laboratory analysis at least 80 g of surface material from the nucleus of comet 67P/Churyumov-Gerasimenko (hereafter 67P). CAESAR will characterize the surface region sampled, preserve the sample in a pristine state, and return evolved volatiles by capturing them in a separate gas reservoir. The system protects both volatile and non-volatile components from contamination or alteration thatwould hamper their scientific analysis. Laboratory analyses of comet samples provide unparalleled knowledge about the presolar history through the initial stages of planet formation to the origin of life.

Published
2018

8. The Mars Atmosphere and Volatile Evolution (MAVEN) Mission

Author

Jakosky, B. M., Lin, R. P., Grebowsky, J. M., Luhmann, J. G., Mitchell, D. F., Beutelschies, G., Priser, T., Acuna, M., Andersson, L., Baird, D., Baker, D., Bartlett, R., Benna, M., Bougher, S., Brain, D., Carson, D., Cauffman, S., Chamberlin, P., Chaufray, J.-Y., Cheatom, O., Clarke, J., Connerney, J., Cravens, T., Curtis, D., Delory, G., Demcak, S., DeWolfe, A., Eparvier, F., Ergun, R., Eriksson, A., Espley, J., Fang, X., Folta, D., Fox, J., Gomez-Rosa, C., Habenicht, S., Halekas, J., Holsclaw, G., Houghton, M., Howard, R., Jarosz, M., Jedrich, N., Johnson, M., Kasprzak, W., Kelley, M., King, T., Lankton, M., Larson, D., Leblanc, F., Lefevre, F., Lillis, R., Mahaffy, P., Mazelle, C., McClintock, W., McFadden, J., Mitchell, D. L., Montmessin, F., Morrissey, J., Peterson, W., Possel, W., Sauvaud, J.-A., Schneider, N., Sidney, W., Sparacino, S., Stewart, A. I. F., Tolson, R., Toublanc, D., Waters, C., Woods, T., Yelle, R., and Zurek, R.

Published
2015
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9. Strategies and Prospects for Vaccination Against the Hepatitis C Viruses

Author

Houghton, M., Compans, R. W., editor, Cooper, M., editor, Hogle, J. M., editor, Ito, Y., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M., editor, Olsnes, S., editor, Potter, M., editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, Hagedorn, Curt H., editor, and Rice, Charles M., editor

Published
2000
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24. Vaccination of chimpanzees against infection by the hepatitis C virus

Author

Choo, Q.-L., Kuo, G., Ralston, R., Weiner, A., Chien, D., Van Nest, G., Berger, K., Han, J., Thudium K., Kuo, C., Kansopon, J., McFarland, J., Tabrizi, A., Ching, K., Moss, B., Cummins, L.B., Houghton, M., and Muchmore, E.

Subjects
Hepatitis C virus, HeLa cells -- Research, Glycoproteins -- Research, Science and technology
Abstract

Putative envelope glycoproteins, E1(gp33) and E2(gp72), copurified from HeLa cells infected with a recombinant vaccinia virus expression vector, were used to immunize seven chimpanzees. All vaccines exhibited a powerful humoral immune response. Total protection against an i.v. challenge with homologous hepatitis 6 virus 1 was evident in the five highest responders.

Published
1994

25. Thruster Placement Issues and Possible Mitigation Methods for the ST-7 Disturbance Reduction System

Author

Hsu, O, Markley, L, Houghton, M, and Maghami, P

Subjects
Spacecraft Propulsion And Power
Abstract

The Space Technology-7 Disturbance Reduction System is being designed to demonstrate the ability to shield a test mass from non-gravitational forces. In order to meet this goal, two advanced technologies will be employed: a highly sensitive Gravitational Reference Sensor and micro-Newton thrusters. ST-7 is limited to two clusters of four thrusters, which are sufficient to provide control for 6 degrees of freedom, but the overall effectiveness of the baseline configuration is limited by the noise on the measurement signals and the thrust outputs, the disturbance force caused by solar radiation pressure, and the performance of the individual thrusters. This paper presents and discusses these issues in greater detail along with possible mitigation methods.

Published
2004

26. 18-Degree-of-Freedom Controller Design for the ST7 Disturbance Reduction System

Author

Markley, F. L, Maghami, P. G, Houghton, M. B, and Hsu, O. C

Subjects
Aircraft Stability And Control
Abstract

The Space Technology 7 experiment will perform an on-orbit system-level validation of a Disturbance Reduction System employing gravitational reference sensors and micronewton colloidal thrusters to maintain a spacecraft s position with respect to free-floating test masses in the gravitational reference sensors to less than 10 nm/dHz over the frequency range 1 to 30 mHz. This paper presents the design and analysis of the control system that closes the loop between the gravitational reference sensors and the micronewton thrusters while incorporating star tracker data at low frequencies. The effects of disturbances and actuation and measurement noise are evaluated in a eighteen-degree-of-freedom model.

Published
2003

27. Design and Analysis of the ST7 Disturbance Reduction System (DRS) Spacecraft Controller

Author

Maghami, P. G, Markley, F. L, Houghton, M. B, and Dennehy, C. J

Subjects
Spacecraft Design, Testing And Performance
Abstract

The Space Technology 7 experiment will perform an on-orbit system-level validation of two specific Disturbance Reduction System technologies: a gravitational reference sensor employing a free-floating test mass and a set of micronewton colloidal thrusters. The Disturbance Reduction System is designed to maintain a spacecraft's position with respect to the free-floating test mass to less than 10 nm/square root of Hz, over the frequency range 10(exp -3) Hz to 10(exp -2) Hz. This paper presents the design and analysis of the coupled drag-free and attitude control system that closes the loop between the gravitational reference sensor and the micronewton thrusters while incorporating star tracker data at low frequencies. The effects of actuation and measurement noise and disturbances on the spacecraft and test masses are evaluated in a seven-degree-of-freedom planar model incorporating two translational and one rotational degrees of freedom for the spacecraft and two translational degrees of freedom for each test mass.

Published
2003

28. Disturbance Reduction Control Design for the ST7 Flight Validation Experiment

Author

Maghami, P. G, Hsu, O. C, Markley, F. L, and Houghton, M. B

Subjects
Spacecraft Design, Testing And Performance
Abstract

The Space Technology 7 experiment will perform an on-orbit system-level validation of two specific Disturbance Reduction System technologies: a gravitational reference sensor employing a free-floating test mass, and a set of micro-Newton colloidal thrusters. The ST7 Disturbance Reduction System is designed to maintain the spacecraft's position with respect to a free-floating test mass to less than 10 nm/Hz, over the frequency range of 1 to 30 mHz. This paper presents the design and analysis of the coupled, drag-free and attitude control systems that close the loop between the gravitational reference sensor and the micro-Newton thrusters, while incorporating star tracker data at low frequencies. A full 18 degree-of-freedom model, which incorporates rigid-body models of the spacecraft and two test masses, is used to evaluate the effects of actuation and measurement noise and disturbances on the performance of the drag-free system.

Published
2003

29. ST7-DRS: A Step Towards Drag-free and High-precision Formation Control

Author

Houghton, M, Folkner, W, Hanson, J, and Hruby, V

Subjects
Spacecraft Design, Testing And Performance
Abstract

The Space Technology 7 Disturbance Reduction System (ST7-DRS) is an in-space technology demonstration within NASA's New Millennium Program. ST7-DRS is designed to validate system-level technologies that are required for future gravity missions (including the planned LISA gravitational-wave observatory) and for future formation-flying interferometer missions (including the planned MAXIM black-hole imager). ST7-DRS is based around a freely-floating test mass contained within a spacecraft structure that will shield this test mass from all external forces (aside from gravity). The spacecraft position will be continuously controlled, such that the spacecraft, itself, will remain centered about this test mass, essentially flying in formation with it. Colloidal micro-thrusters will be used to control the spacecraft s position to within a few nanometers, over time scales of tens to thousands of seconds. In order to detect the residual acceleration noise on the main test mass, a second test mass will be flown alongside the first, within the same physical spacecraft structure. This test mass will serve as a cross-reference for the first, and will also be used as a reference for the spacecraft's attitude control. The spacecraft's attitude will be controlled to an accuracy of a few milli-arc-seconds, also utilizing the colloidal micro-thrusters. ST7-DRS will consist of an instrument package (containing the test masses) and a set of micro-thrusters, which will be attached to the European Space Agency s SMART-2 spacecraft, set to launch in November 2007.

Published
2003

30. Disturbance reduction system: testing technology for precision formation control

Author

Spero, R, Prakash, S, Miller, D, Maghami, P, Houghton, M, Markley, F. L, Kuhnert, A, Keiser, G. M, Hruby, V, Hanson, J, Gamero-Castano, M, Dennehy, C. J, DeBra, D, Byer, R. L, Buchman, S, and Folkner, W. M

Abstract

The Disturbance Reduction System (DRS) is a space technology demonstration within NASA's New Millenium Program.

Published
2002

36. Global Demand for Natural Resources EliminatedMore Than 100,000 Bornean Orangutans

Author

Voigt, M, Wich, SA, Ancrenaz, M, Meijaard, E, Abram, N, Banes, GL, Campbell-Smith, G, d'Arcy, LJ, Delgado, RA, Erman, A, Gaveau, D, Goossens, B, Heinicke, S, Houghton, M, Husson, SJ, Leiman, A, Sanchez, KL, Makinuddin, N, Marshall, AJ, Meididit, A, Miettinen, J, Mundry, R, Musnanda, Nardiyono, Nurcahyo, A, Odom, K, Panda, A, Prasetyo, D, Priadjati, A, Purnomo, Rafiastanto, A, Russon, AE, Santika, T, Sihite, J, Spehar, S, Struebig, M, Sulbaran-Romero, E, Tjiu, A, Wells, J, Wilson, KA, Kuehl, HS, Voigt, M, Wich, SA, Ancrenaz, M, Meijaard, E, Abram, N, Banes, GL, Campbell-Smith, G, d'Arcy, LJ, Delgado, RA, Erman, A, Gaveau, D, Goossens, B, Heinicke, S, Houghton, M, Husson, SJ, Leiman, A, Sanchez, KL, Makinuddin, N, Marshall, AJ, Meididit, A, Miettinen, J, Mundry, R, Musnanda, Nardiyono, Nurcahyo, A, Odom, K, Panda, A, Prasetyo, D, Priadjati, A, Purnomo, Rafiastanto, A, Russon, AE, Santika, T, Sihite, J, Spehar, S, Struebig, M, Sulbaran-Romero, E, Tjiu, A, Wells, J, Wilson, KA, and Kuehl, HS

Abstract

Unsustainable exploitation of natural resources is increasingly affecting the highly biodiverse tropics [1, 2]. Although rapid developments in remote sensing technology have permitted more precise estimates of land-cover change over large spatial scales [3-5], our knowledge about the effects of these changes on wildlife is much more sparse [6, 7]. Here we use field survey data, predictive density distribution modeling, and remote sensing to investigate the impact of resource use and land-use changes on the density distribution of Bornean orangutans (Pongo pygmaeus). Our models indicate that between 1999 and 2015, half of the orangutan population was affected by logging, deforestation, or industrialized plantations. Although land clearance caused the most dramatic rates of decline, it accounted for only a small proportion of the total loss. A much larger number of orangutans were lost in selectively logged and primary forests, where rates of decline were less precipitous, but where far more orangutans are found. This suggests that further drivers, independent of land-use change, contribute to orangutan loss. This finding is consistent with studies reporting hunting as a major cause in orangutan decline [8-10]. Our predictions of orangutan abundance loss across Borneo suggest that the population decreased by more than 100,000 individuals, corroborating recent estimates of decline [11]. Practical solutions to prevent future orangutan decline can only be realized by addressing its complex causes in a holistic manner across political and societal sectors, such as in land-use planning, resource exploitation, infrastructure development, and education, and by increasing long-term sustainability [12]. VIDEO ABSTRACT.

Published
2018

39. First integrative trend analysis for a great ape species in Borneo

Author

Santika, T, Ancrenaz, M, Wilson, KA, Spehar, S, Abram, N, Banes, GL, Campbell-Smith, G, Curran, L, d'Arcy, L, Delgado, RA, Erman, A, Goossens, B, Hartanto, H, Houghton, M, Husson, SJ, Kuehl, HS, Lackman, I, Leiman, A, Sanchez, KL, Makinuddin, N, Marshall, AJ, Meididit, A, Mengersen, K, Nardiyono, M, Nurcahyo, A, Odom, K, Panda, A, Prasetyo, D, Purnomo, Rafiastanto, A, Raharjo, S, Ratnasari, D, Russon, AE, Santana, AH, Santoso, E, Sapari, I, Sihite, J, Suyoko, A, Tjiu, A, Utami-Atmoko, SS, van Schaik, CP, Voigt, M, Wells, J, Wich, SA, Willems, EP, Meijaard, E, Santika, T, Ancrenaz, M, Wilson, KA, Spehar, S, Abram, N, Banes, GL, Campbell-Smith, G, Curran, L, d'Arcy, L, Delgado, RA, Erman, A, Goossens, B, Hartanto, H, Houghton, M, Husson, SJ, Kuehl, HS, Lackman, I, Leiman, A, Sanchez, KL, Makinuddin, N, Marshall, AJ, Meididit, A, Mengersen, K, Nardiyono, M, Nurcahyo, A, Odom, K, Panda, A, Prasetyo, D, Purnomo, Rafiastanto, A, Raharjo, S, Ratnasari, D, Russon, AE, Santana, AH, Santoso, E, Sapari, I, Sihite, J, Suyoko, A, Tjiu, A, Utami-Atmoko, SS, van Schaik, CP, Voigt, M, Wells, J, Wich, SA, Willems, EP, and Meijaard, E

Abstract

For many threatened species the rate and drivers of population decline are difficult to assess accurately: species' surveys are typically restricted to small geographic areas, are conducted over short time periods, and employ a wide range of survey protocols. We addressed methodological challenges for assessing change in the abundance of an endangered species. We applied novel methods for integrating field and interview survey data for the critically endangered Bornean orangutan (Pongo pygmaeus), allowing a deeper understanding of the species' persistence through time. Our analysis revealed that Bornean orangutan populations have declined at a rate of 25% over the last 10 years. Survival rates of the species are lowest in areas with intermediate rainfall, where complex interrelations between soil fertility, agricultural productivity, and human settlement patterns influence persistence. These areas also have highest threats from human-wildlife conflict. Survival rates are further positively associated with forest extent, but are lower in areas where surrounding forest has been recently converted to industrial agriculture. Our study highlights the urgency of determining specific management interventions needed in different locations to counter the trend of decline and its associated drivers.

Published
2017

41. HCV E1E2-MF59 vaccine in chronic hepatitis C patients treated with PEG-IFNα2a and Ribavirin: a randomized controlled trial

Author

Almasio, P., Colombatto, P., Brunetto, M., Maina, A., Romagnoli, V., Rumi, M., Ascione, A., Pinzello, G., Mondelli, M., Muratori, L., Rappuoli, R., Rosa, D., Houghton, M., Abrignani, S., Bonino, F., Almasio, PL, Colombatto, P, Brunetto, MR, Maina, AM, Romagnoli, V, Almasio, P, Rumi, MG, Ascione, A, Pinzello, G, Mondelli, M, Muratori, L, Rappuoli, R, Rosa, D, Houghton, M, Abrignani, S, and Bonino, F

Subjects
HCV vaccine
Abstract

Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV-specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy-eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon-(IFN)/ribavirin-(RBV)] were randomly assigned to vaccine (V:23), Peg-IFNα2a-180-ug/qw and ribavirin 1000-1200-mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0-4-8-12-24-28-32-36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2-specific-CD4 + T cells were performed at week 0-12-16-48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and

Published
2014

42. Confirmation of hepatitis C virus infection by new four-antigen recombinant immunoblot assay

Author

van der Poel, C.L., Cuypers, H.T.M., Reesink, H.W., Weiner, A.J., Quan, S., Nello, R.di, Boven, J.J.P.van, Winkel, I., Mulder-Fokerts, D., Exel-Oehlers, P.J., Schaasberg, W., Leentvaar-Kuypers, A, Polito, A., Houghton, M., and Lelie, P.N.

Subjects
Hepatitis C virus, Immunoenzyme technique -- Innovations, Enzyme-linked immunosorbent assay
Published
1991

43. Hepatitis C antibody and chronic liver disease in haemophilia

Author

Makris, M., Preston, F.E., Triger, D.R., Underwood, J.C.E., Choo, Q.L., Kuo, G., and Houghton, M.

Subjects
Blood clotting disorders, Hemophilia -- Complications, Liver diseases, Hepatitis E -- Diagnosis, Hepatitis E -- Causes of
Published
1990

44. HCV E1E2-MF59vaccine in chronic hepatitis C patients treated with PEG-IFNα2a and Ribavirin: a randomized controlled trial

Author

Colombatto, P, Brunetto, M R, Maina, A M, Romagnoli, V, Almasio, P, Rumi, M G, Ascione, A, Pinzello, G, Mondelli, M, Muratori, L, Rappuoli, R, Rosa, D, Houghton, M, Abrignani, S, Bonino, F, P. Colombatto, M. R. Brunetto, A. M. Maina, V. Romagnoli, P. Almasio, M. G. Rumi, A. Ascione, G. Pinzello, M. Mondelli, L. Muratori, R. Rappuoli, D. Rosa, M. Houghton, S. Abrignani, and F. Bonino

Subjects
CD4-Positive T-Lymphocytes, Squalene, Viral Hepatitis Vaccines, Drug-Related Side Effects and Adverse Reactions, viral kinetics, Polysorbates, VACCINE, Antiviral Agents, Injections, Intramuscular, immune response, Polyethylene Glycols, viral kinetic, Adjuvants, Immunologic, Ribavirin, Humans, neutralizing antibodies, HCV, interferon, vaccine, Cell Proliferation, Vaccines, Synthetic, Interferon-alpha, Original Articles, Hepatitis C Antibodies, Hepatitis C, Chronic, Viral Load, Antibodies, Neutralizing, Combined Modality Therapy, Recombinant Proteins, Treatment Outcome, RNA, Viral
Abstract

Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV-specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy-eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon-(IFN)/ribavirin-(RBV)] were randomly assigned to vaccine (V:23), Peg-IFNα2a-180-ug/qw and ribavirin 1000–1200-mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0-4-8-12-24-28-32-36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2-specific-CD4 + T cells were performed at week 0-12-16-48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and

Published
2014

47. The 3rd Canadian symposium on Hepatitis c Virus: Expanding care in the interferon-free era

Author

MacParland, SA, Bilodeau, M, Grebely, J, Bruneau, J, Cooper, C, Klein, M, Sagan, SM, Choucha, N, Balfour, L, Bialystok, F, Krajden, M, Raven, J, Roberts, E, Russell, R, Houghton, M, Tyrrell, DL, Feld, JJ, Butt, G, Conway, B, Edwards, A, Fischer, B, Götte, M, Kneteman, N, Krahn, M, Levy, G, Liu, Q, McGilvray, I, Michalak, T, Mugford, G, Myers, R, Ostrowski, M, Pause, A, Pezacki, J, Richardson, C, Schang, L, Shoukry, N, Sonenberg, N, Soudeyns, H, Tellier, R, Tyndall, M, Wilson, J, Boisvert, M, Depla, M, Dupont, B, Ehteshami, M, Issur, M, Olmstead, A, Sarhan, M, Siu, R, Van Buuren, N, Ablenas, C, Bernier, A, Cunningham, E, Fabre, T, Fahmy, A, Hoffman, B, Hyrina, A, Kofahi, H, Kulkarni, A, Moqueet, N, Ardakan, NN, Singaravelu, R, Thibault, P, Wu, Q, Artenie, A, Puzhko, S, Saeed, S, Taylor, N, Wong, J, Cumming, A, MacParland, SA, Bilodeau, M, Grebely, J, Bruneau, J, Cooper, C, Klein, M, Sagan, SM, Choucha, N, Balfour, L, Bialystok, F, Krajden, M, Raven, J, Roberts, E, Russell, R, Houghton, M, Tyrrell, DL, Feld, JJ, Butt, G, Conway, B, Edwards, A, Fischer, B, Götte, M, Kneteman, N, Krahn, M, Levy, G, Liu, Q, McGilvray, I, Michalak, T, Mugford, G, Myers, R, Ostrowski, M, Pause, A, Pezacki, J, Richardson, C, Schang, L, Shoukry, N, Sonenberg, N, Soudeyns, H, Tellier, R, Tyndall, M, Wilson, J, Boisvert, M, Depla, M, Dupont, B, Ehteshami, M, Issur, M, Olmstead, A, Sarhan, M, Siu, R, Van Buuren, N, Ablenas, C, Bernier, A, Cunningham, E, Fabre, T, Fahmy, A, Hoffman, B, Hyrina, A, Kofahi, H, Kulkarni, A, Moqueet, N, Ardakan, NN, Singaravelu, R, Thibault, P, Wu, Q, Artenie, A, Puzhko, S, Saeed, S, Taylor, N, Wong, J, and Cumming, A

Abstract

Hepatitis C virus (HCV) currently infects approximately 250,000 individuals in Canada and causes more years of life lost than any other infectious disease in the country. In August 2011, new therapies were approved by Health Canada that have achieved higher response rates among those treated, but are poorly tolerated. By 2014/2015, shortcourse, well-tolerated treatments with cure rates >95% will be available. However, treatment uptake is poor due to structural, financial, geographical, cultural and social barriers. As such, 'Barriers to access to HCV care in Canada' is a crucial topic that must be addressed to decrease HCV disease burden and potentially eliminate HCV in Canada. Understanding how to better care for HCV-infected individuals requires integration across multiple disciplines including researchers, clinical services and policy makers to address the major populations affected by HCV including people who inject drugs, baby boomers, immigrants and Aboriginal and/or First Nations people. In 2012, the National CIHR Research Training Program in Hepatitis C organized the 1st Canadian Symposium on Hepatitis C Virus (CSHCV) in Montreal, Quebec. The 2nd CSHCV was held in 2013 in Victoria, British Columbia. Both symposia were highly successful, attracting leading international faculty with excellent attendance leading to dialogue and knowledge translation among attendees of diverse backgrounds. The current article summarizes the 3rd CSHCV, held February 2014, in Toronto, Ontario.

Published
2014

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