- Email: [email protected]
90. Can indoleamine 2,3-dioxygenase (IDO) be targeted to improve tumor clearance as well as attenuate cancer-related symptoms?
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Abstracts from the 21st Annual PNIRS Meeting 40 (2014) e1–e52
pro-inflammatory environment that results in neuronal dysfunction and ultimately behavioral deficits in autism. http://dx.doi.org/10.1016/j.bbi.2014.06.107
88. The impact of workload and training status on salivary antimicrobial proteins following acute exercise H.E. Kunz, G. Spielmann, M. Pistillo, J. Reed, T. Ograjsek, R.J. Simpson Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA Salivary antimicrobial proteins (sAMPs) protect the upper respiratory tract from invading microorganisms. Maintaining mucosal immune integrity is important for elite-level endurance athletes as high levels of training are associated with increased risks of upper respiratory tract infection (URTI). This study examined the effects of exercising workload and training status on the sAMP response to acute exercise. Seventeen trained cyclists completed three 30min exercise trials at 5%, +5% and +15% of the individual blood lactate threshold (BLT). Saliva samples were collected pre and postexercise to determine the concentration and secretion of a-amylase, HNP1–3, lactoferrin, LL-37, lysozyme, and sIgA. The concentration and/or secretion of all sAMPs increased post-exercise, but only aamylase was sensitive to exercise workload. Highly trained cyclists (BLT power output/kg body mass > 2.8 w) had lower baseline concentrations of a-amylase, HNP1–3, and lactoferrin, although no group differences were found for baseline sAMP secretion rates. Highly trained cyclists did, however, exhibit greater post-exercise increases in the concentration and/or secretion of all measured sAMPs. This study shows that acute dynamic exercise increases sAMP concentration and secretion, and that a-amylase is sensitive marker of the sympathetic response that is associated with different exercising workloads. We also show for the first time that training status is a major determinant of both resting and exercise-induced changes in sAMPs, indicating a potential adaptive response to acute exercise in highly trained athletes. http://dx.doi.org/10.1016/j.bbi.2014.06.108
89. Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice E.G. Vichaya, S.C. Hunt, R. Dantzer UT MD Anderson Cancer Center, Symptom Research, 1400 Pressler Unit 1450, Houston, TX 77030, USA Inflammation has been implicated in the development of various disorders, including fatigue and depression. However, the neurobehavioral mechanism involved in this relationship remains elusive. This gap in knowledge may best be filled by evaluating elementary neurobehavioral processes affected by inflammation rather than just behavioral changes in conventional animal tests of depression. To this end the current study used a concurrent choice paradigm to evaluate inflammation-induced alterations in incentive motivation. Mice were food restricted to between 85% and 90% of their free feeding weight and were trained to perform a concurrent choice task where they nose poked for grain rewards on a fixed ratio 1 schedule (low effort/low reward) and chocolate-flavored rewards on a fixed ratio 10 schedule (high effort/high reward). A counterbalanced within subjects design was used. A single injection of 0.33 mg/kg lipopolysaccharide was used to induce peripheral inflammation. Twenty-four hours after lipopolysaccharide administration mice showed a reduction in the total number of nose pokes. A proportionally greater
reduction in nose pokes was observed for grain, resulting in an increase in percent chocolate pellets earned. These behavioral changes are not due to reduced appetite as pre-feeding led to a similar increase in percent chocolate pellets earned but without any decrease in responding. These results indicate that inflammation modulates incentive motivation by affecting willingness to exert effort for reward and not by reducing sensitivity to reward. http://dx.doi.org/10.1016/j.bbi.2014.06.109
90. Can indoleamine 2,3-dioxygenase (IDO) be targeted to improve tumor clearance as well as attenuate cancer-related symptoms? E.G. Vichaya a, D.W. Vermeer b, A. Kavelaars a, J.H. Lee b, R. Dantzer a a
UT MD Anderson Cancer Center, Symptom Research, 1400 Pressler Unit 1450, Houston, TX 77030, USA b Sanford Research, Sioux Falls, SD, USA The tryptophan degrading enzyme IDO is expressed by tumor cells and immune cells in the tumor microenvironment. This creates a tolerogenic milieu that compromises tumor clearance. Further, IDO has been shown to be involved in cancer-related fatigue and inflammation-associated depression. As many cancer patients suffer from these symptoms, we sought to determine if inhibiting IDO using 1methyl-L-tryptophan (1-MT) could improve tumor clearance and attenuate symptoms. C57BL/6J mice were injected with 1 106 tumor cells into the right hind leg to model HPV + head and neck cancer and 7 days later treated with 20 mg/m2 cisplatin and 8 Gy irradiation once weekly for three weeks. Half of the mice were provided 1-MT treated drinking water (5 mg/ml) beginning 2 days prior to tumor cell injection. 1-MT treatment decreased IDO activity as measured by the serum kynurenine/tryptophan ratio, and this was associated with decreased tumor growth and a trend toward improved survival. In a follow up study, burrowing (a sensitive behavioral measure of sickness) was measured before and after implantation of the tumor and during chemoradiation. Burrowing decreased over time and this effect was more pronounced in 1-MT treated mice. This data suggests that although targeting IDO may improve tumor clearance, it might also exacerbate cancer-related symptoms probably as a consequence of immune reactivation. A follow up study is currently underway to confirm these findings. http://dx.doi.org/10.1016/j.bbi.2014.06.110
91. Early-life LPS administrations induce cognitive decline and changes in NMDA receptor subunit gene expression in the rodent brain K.J. Fomalont a, E.A. Veniaminova a, S.V. Kalemenev b, A.N. Trofimov a, A.P. Schwarz a, O.E. Zubareva a a
Institute of Experimental Medicine of the Northwest Branch of the Russian Academy of Medical Sciences, St. Petersburg, Russia b Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Russia The aim of this work was to investigate the effect of neonatal bacterial infections on NMDA receptor subunit composition underlying exploratory behavior and spatial memory. Male Wistar rats were treated with saline or bacterial lipopolysaccharide (LPS, 25 l/kg) intraperitoneally at PND 14, 16, and 18, and a control group was left intact. Behavioral testing was performed on PND 22–29 in the Open Field and the Morris water maze. The mRNA expression of NR1, NR2A, NR2B, NR2C, and NR2D subunits of NMDA receptors in medial
Abstracts from the 21st Annual PNIRS Meeting 40 (2014) e1–e52
pro-inflammatory environment that results in neuronal dysfunction and ultimately behavioral deficits in autism. http://dx.doi.org/10.1016/j.bbi.2014.06.107
88. The impact of workload and training status on salivary antimicrobial proteins following acute exercise H.E. Kunz, G. Spielmann, M. Pistillo, J. Reed, T. Ograjsek, R.J. Simpson Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, USA Salivary antimicrobial proteins (sAMPs) protect the upper respiratory tract from invading microorganisms. Maintaining mucosal immune integrity is important for elite-level endurance athletes as high levels of training are associated with increased risks of upper respiratory tract infection (URTI). This study examined the effects of exercising workload and training status on the sAMP response to acute exercise. Seventeen trained cyclists completed three 30min exercise trials at 5%, +5% and +15% of the individual blood lactate threshold (BLT). Saliva samples were collected pre and postexercise to determine the concentration and secretion of a-amylase, HNP1–3, lactoferrin, LL-37, lysozyme, and sIgA. The concentration and/or secretion of all sAMPs increased post-exercise, but only aamylase was sensitive to exercise workload. Highly trained cyclists (BLT power output/kg body mass > 2.8 w) had lower baseline concentrations of a-amylase, HNP1–3, and lactoferrin, although no group differences were found for baseline sAMP secretion rates. Highly trained cyclists did, however, exhibit greater post-exercise increases in the concentration and/or secretion of all measured sAMPs. This study shows that acute dynamic exercise increases sAMP concentration and secretion, and that a-amylase is sensitive marker of the sympathetic response that is associated with different exercising workloads. We also show for the first time that training status is a major determinant of both resting and exercise-induced changes in sAMPs, indicating a potential adaptive response to acute exercise in highly trained athletes. http://dx.doi.org/10.1016/j.bbi.2014.06.108
89. Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice E.G. Vichaya, S.C. Hunt, R. Dantzer UT MD Anderson Cancer Center, Symptom Research, 1400 Pressler Unit 1450, Houston, TX 77030, USA Inflammation has been implicated in the development of various disorders, including fatigue and depression. However, the neurobehavioral mechanism involved in this relationship remains elusive. This gap in knowledge may best be filled by evaluating elementary neurobehavioral processes affected by inflammation rather than just behavioral changes in conventional animal tests of depression. To this end the current study used a concurrent choice paradigm to evaluate inflammation-induced alterations in incentive motivation. Mice were food restricted to between 85% and 90% of their free feeding weight and were trained to perform a concurrent choice task where they nose poked for grain rewards on a fixed ratio 1 schedule (low effort/low reward) and chocolate-flavored rewards on a fixed ratio 10 schedule (high effort/high reward). A counterbalanced within subjects design was used. A single injection of 0.33 mg/kg lipopolysaccharide was used to induce peripheral inflammation. Twenty-four hours after lipopolysaccharide administration mice showed a reduction in the total number of nose pokes. A proportionally greater
reduction in nose pokes was observed for grain, resulting in an increase in percent chocolate pellets earned. These behavioral changes are not due to reduced appetite as pre-feeding led to a similar increase in percent chocolate pellets earned but without any decrease in responding. These results indicate that inflammation modulates incentive motivation by affecting willingness to exert effort for reward and not by reducing sensitivity to reward. http://dx.doi.org/10.1016/j.bbi.2014.06.109
90. Can indoleamine 2,3-dioxygenase (IDO) be targeted to improve tumor clearance as well as attenuate cancer-related symptoms? E.G. Vichaya a, D.W. Vermeer b, A. Kavelaars a, J.H. Lee b, R. Dantzer a a
UT MD Anderson Cancer Center, Symptom Research, 1400 Pressler Unit 1450, Houston, TX 77030, USA b Sanford Research, Sioux Falls, SD, USA The tryptophan degrading enzyme IDO is expressed by tumor cells and immune cells in the tumor microenvironment. This creates a tolerogenic milieu that compromises tumor clearance. Further, IDO has been shown to be involved in cancer-related fatigue and inflammation-associated depression. As many cancer patients suffer from these symptoms, we sought to determine if inhibiting IDO using 1methyl-L-tryptophan (1-MT) could improve tumor clearance and attenuate symptoms. C57BL/6J mice were injected with 1 106 tumor cells into the right hind leg to model HPV + head and neck cancer and 7 days later treated with 20 mg/m2 cisplatin and 8 Gy irradiation once weekly for three weeks. Half of the mice were provided 1-MT treated drinking water (5 mg/ml) beginning 2 days prior to tumor cell injection. 1-MT treatment decreased IDO activity as measured by the serum kynurenine/tryptophan ratio, and this was associated with decreased tumor growth and a trend toward improved survival. In a follow up study, burrowing (a sensitive behavioral measure of sickness) was measured before and after implantation of the tumor and during chemoradiation. Burrowing decreased over time and this effect was more pronounced in 1-MT treated mice. This data suggests that although targeting IDO may improve tumor clearance, it might also exacerbate cancer-related symptoms probably as a consequence of immune reactivation. A follow up study is currently underway to confirm these findings. http://dx.doi.org/10.1016/j.bbi.2014.06.110
91. Early-life LPS administrations induce cognitive decline and changes in NMDA receptor subunit gene expression in the rodent brain K.J. Fomalont a, E.A. Veniaminova a, S.V. Kalemenev b, A.N. Trofimov a, A.P. Schwarz a, O.E. Zubareva a a
Institute of Experimental Medicine of the Northwest Branch of the Russian Academy of Medical Sciences, St. Petersburg, Russia b Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Russia The aim of this work was to investigate the effect of neonatal bacterial infections on NMDA receptor subunit composition underlying exploratory behavior and spatial memory. Male Wistar rats were treated with saline or bacterial lipopolysaccharide (LPS, 25 l/kg) intraperitoneally at PND 14, 16, and 18, and a control group was left intact. Behavioral testing was performed on PND 22–29 in the Open Field and the Morris water maze. The mRNA expression of NR1, NR2A, NR2B, NR2C, and NR2D subunits of NMDA receptors in medial