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Article: The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy.

Chacon, Jessica Ann / Schutsky, Keith / Powell, Daniel J

2016 Volume 4, Issue 4

Abstract: Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune ... ...

Abstract	Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules.
Language	English
Publishing date	2016-11-14
Publishing country	Switzerland
Document type	Review ; Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines4040043
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling.

Schutsky, Keith / Ouyang, Ming / Thomas, Steven A

Learning & memory (Cold Spring Harbor, N.Y.)

2011 Volume 18, Issue 9, Page(s) 598–604

Abstract: Xamoterol, a partial β(1)-adrenergic receptor agonist, has been reported to impair the retrieval of hippocampus-dependent spatial reference memory in rats. In contrast, xamoterol restores memory retrieval in gene-targeted mice lacking norepinephrine (NE) ...

Abstract	Xamoterol, a partial β(1)-adrenergic receptor agonist, has been reported to impair the retrieval of hippocampus-dependent spatial reference memory in rats. In contrast, xamoterol restores memory retrieval in gene-targeted mice lacking norepinephrine (NE) and in a transgenic mouse model of Down syndrome in which NE levels are reduced. Restoration of retrieval by xamoterol in these two models complements the observation that NE and β(1) signaling are required for hippocampus-dependent retrieval of contextual and spatial reference memory in wild-type mice and rats. Additional evidence indicates that cAMP-mediated PKA and Epac signaling are required for the retrieval of hippocampus-dependent memory. As a result, we hypothesized that xamoterol has effects in addition to the stimulation of β(1) receptors that, at higher doses, act to counter the effects of β(1) signaling. Here we report that xamoterol-induced disruption of memory retrieval depends on β(2)-adrenergic receptor signaling. Interestingly, the impairment of memory retrieval by xamoterol is blocked by pretreatment with pertussis toxin, an uncoupling agent for G(i/o) signaling, suggesting that β(2) signaling opposes β(1) signaling during memory retrieval at the level of G protein and cAMP signaling. Finally, similar to the time-dependent roles for NE, β(1), and cAMP signaling in hippocampus-dependent memory retrieval, xamoterol only impairs retrieval for several days after training, indicating that its effects are also limited by the age of the memory. We conclude that the disruption of memory retrieval by xamoterol is mediated by G(i/o)-coupled β(2) signaling, which opposes the G(s)-coupled β(1) signaling that is transiently required for hippocampus-dependent emotional memory retrieval.
MeSH term(s)	Adrenergic beta-1 Receptor Agonists/adverse effects ; Adrenergic beta-Antagonists/pharmacology ; Analysis of Variance ; Animals ; Behavior, Animal/drug effects ; Chi-Square Distribution ; Conditioning, Classical/drug effects ; Conditioning, Operant/drug effects ; Dose-Response Relationship, Drug ; Emotions/drug effects ; Fear/drug effects ; Fear/physiology ; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism ; Hippocampus/drug effects ; Hippocampus/physiology ; Memory Disorders/chemically induced ; Memory Disorders/pathology ; Mental Recall/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pertussis Toxin/pharmacology ; Propanolamines/pharmacology ; Receptors, Adrenergic, beta-1/deficiency ; Receptors, Adrenergic, beta-2/deficiency ; Receptors, Adrenergic, beta-2/metabolism ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Time Factors ; Xamoterol/adverse effects
Chemical Substances	Adrenergic beta-1 Receptor Agonists ; Adrenergic beta-Antagonists ; Propanolamines ; Receptors, Adrenergic, beta-1 ; Receptors, Adrenergic, beta-2 ; ICI 118551 (46OL1UC10R) ; Xamoterol (7HE0JQL703) ; Pertussis Toxin (EC 2.4.2.31) ; GTP-Binding Protein alpha Subunits, Gi-Go (EC 3.6.5.1)
Language	English
Publishing date	2011-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1204777-6
ISSN	1549-5485 ; 1072-0502
ISSN (online)	1549-5485
ISSN	1072-0502
DOI	10.1101/lm.2302811
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Article ; Online: Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis.

Edavettal, Suzanne / Cejudo-Martin, Pilar / Dasgupta, Bidisha / Yang, Danlin / Buschman, Matthew D / Domingo, Derrick / Van Kolen, Kristof / Jaiprasat, Pharavee / Gordon, Renata / Schutsky, Keith / Geist, Brian / Taylor, Natalie / Soubrane, Camille Helene / Van Der Helm, Elisabeth / LaCombe, Ann / Ainekulu, Zemeda / Lacy, Eilyn / Aligo, Jason / Ho, Jason /

He, Yingbo / Lebowitz, Peter F / Patterson, James T / Scheer, Justin M / Singh, Sanjaya

Med (New York, N.Y.)

2022 Volume 3, Issue 12, Page(s) 860–882.e15

Abstract: Background: The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through ... ...

Abstract	Background: The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted. Methods: Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells. Findings: We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion. Conclusions: Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases. Funding: This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.
Language	English
Publishing date	2022-10-17
Publishing country	United States
Document type	Journal Article
ISSN	2666-6340
ISSN (online)	2666-6340
DOI	10.1016/j.medj.2022.09.007
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Article ; Online: Limited brain metabolism changes differentiate between the progression and clearance of rabies virus.

Schutsky, Keith / Portocarrero, Carla / Hooper, D Craig / Dietzschold, Bernhard / Faber, Milosz

PloS one

2014 Volume 9, Issue 4, Page(s) e87180

Abstract: Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue ... ...

Abstract	Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of carnitine and several acylcarnitines, suggesting that these compounds are neuroprotective. The most striking change seen in mock-treated RABV-infected mice was a dramatic increase in brain and serum corticosterone levels, with the later becoming elevated before clinical signs or loss of body weight occurred. We speculate that the rise in corticosterone is part of a strategy of RABV to block the induction of immune responses that would otherwise interfere with its spread. In support of this concept, we show that pharmacological intervention to inhibit corticosterone biosynthesis, in the absence of vaccine treatment, significantly reduces the pathogenicity of RABV. Our results suggest that widespread metabolic changes, including hypothalamic-pituitary-adrenal axis activation, contribute to the pathogenesis of RABV and that preventing these alterations early in infection with PET or pharmacological blockade helps protect brain homeostasis, thereby reducing disease mortality.
MeSH term(s)	3-Hydroxybutyric Acid/metabolism ; Adaptive Immunity ; Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Brain/metabolism ; Brain/virology ; Carnitine/analogs & derivatives ; Carnitine/metabolism ; Corticosterone/blood ; Disease Progression ; Energy Metabolism ; Female ; Gene Expression ; Host-Pathogen Interactions ; Hypothalamo-Hypophyseal System/metabolism ; Hypothalamo-Hypophyseal System/virology ; Mice ; Pituitary-Adrenal System/metabolism ; Pituitary-Adrenal System/virology ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Rabies/drug therapy ; Rabies/immunology ; Rabies/metabolism ; Rabies virus/immunology ; Viral Load ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Viral Vaccines/therapeutic use
Chemical Substances	Antiviral Agents ; Pyridines ; Viral Proteins ; Viral Vaccines ; acylcarnitine ; metapyrone (17286-92-9) ; Carnitine (S7UI8SM58A) ; 3-Hydroxybutyric Acid (TZP1275679) ; Corticosterone (W980KJ009P)
Language	English
Publishing date	2014-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0087180
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Article ; Online: Rigorous optimization and validation of potent RNA CAR T cell therapy for the treatment of common epithelial cancers expressing folate receptor.

Schutsky, Keith / Song, D Gang / Lynn, Rachel / Smith, Jenessa B / Poussin, Mathilde / Figini, Mariangela / Zhao, Yangbing / Powell, Daniel J

Oncotarget

2016 Volume 6, Issue 30, Page(s) 28911–28928

Abstract: Using lentiviral technology, we recently demonstrated that incorporation of CD27 costimulation into CARs greatly improves antitumor activity and T cell persistence. Still, virus-mediated gene transfer is expensive, laborious and enables long-term ... ...

Abstract	Using lentiviral technology, we recently demonstrated that incorporation of CD27 costimulation into CARs greatly improves antitumor activity and T cell persistence. Still, virus-mediated gene transfer is expensive, laborious and enables long-term persistence, creating therapies which cannot be easily discontinued if toxic. To address these concerns, we utilized a non-integrating RNA platform to engineer human T cells to express FRα-specific, CD27 CARs and tested their capacity to eliminate human FRα(+) cancer. Novel CARs comprised of human components were constructed, C4-27z and C4opt-27z, a codon-optimized variant created for efficient expression. Following RNA electroporation, C4-27z and C4opt-27z CAR expression is initially ubiquitous but progressively declines across T cell populations. In addition, C4-27z and C4opt-27z RNA CAR T cells secrete high levels of Th-1 cytokines and display strong cytolytic function against human FRα(+) cancers in a time- and antigen-dependent manner. Further, C4-27z and C4opt-27z CAR T cells exhibit significant proliferation in vivo, facilitate the complete regression of fully disseminated human ovarian cancer xenografts in mice and reduce the progression of solid ovarian cancer. These results advocate for rapid progression of C4opt-27z RNA CAR to the clinic and establish a new paradigm for preclinical optimization and validation of RNA CAR candidates destined for clinical translation.
MeSH term(s)	Animals ; Carcinoma, Ovarian Epithelial ; Cell Line, Tumor ; Cell Proliferation ; Combined Modality Therapy ; Cytokines/immunology ; Cytokines/metabolism ; Cytotoxicity, Immunologic ; Electroporation ; Female ; Folate Receptor 1/immunology ; Folate Receptor 1/metabolism ; Gene Expression Regulation ; Genetic Therapy/methods ; Humans ; Immunotherapy, Adoptive/methods ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Lymphocytes, Tumor-Infiltrating/transplantation ; Mice, Inbred NOD ; Mice, SCID ; Neoplasms, Glandular and Epithelial/genetics ; Neoplasms, Glandular and Epithelial/immunology ; Neoplasms, Glandular and Epithelial/metabolism ; Neoplasms, Glandular and Epithelial/pathology ; Neoplasms, Glandular and Epithelial/therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/immunology ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Ovarian Neoplasms/therapy ; Phenotype ; RNA/genetics ; RNA/metabolism ; Single-Chain Antibodies/genetics ; Single-Chain Antibodies/immunology ; Single-Chain Antibodies/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/transplantation ; Time Factors ; Transfection ; Tumor Burden ; Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics ; Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology ; Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	Cytokines ; FOLR1 protein, human ; Folate Receptor 1 ; Single-Chain Antibodies ; Tumor Necrosis Factor Receptor Superfamily, Member 7 ; RNA (63231-63-0)
Language	English
Publishing date	2016-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.5029
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Article ; Online: Feasibility and Safety of RNA-transfected CD20-specific Chimeric Antigen Receptor T Cells in Dogs with Spontaneous B Cell Lymphoma.

Panjwani, M Kazim / Smith, Jenessa B / Schutsky, Keith / Gnanandarajah, Josephine / O'Connor, Colleen M / Powell, Daniel J / Mason, Nicola J

Molecular therapy : the journal of the American Society of Gene Therapy

2016 Volume 24, Issue 9, Page(s) 1602–1614

Abstract: Preclinical murine models of chimeric antigen receptor (CAR) T cell therapy are widely applied, but are greatly limited by their inability to model the complex human tumor microenvironment and adequately predict safety and efficacy in patients. We ... ...

Abstract	Preclinical murine models of chimeric antigen receptor (CAR) T cell therapy are widely applied, but are greatly limited by their inability to model the complex human tumor microenvironment and adequately predict safety and efficacy in patients. We therefore sought to develop a system that would enable us to evaluate CAR T cell therapies in dogs with spontaneous cancers. We developed an expansion methodology that yields large numbers of canine T cells from normal or lymphoma-diseased dogs. mRNA electroporation was utilized to express a first-generation canine CD20-specific CAR in expanded T cells. The canine CD20 (cCD20) CAR expression was efficient and transient, and electroporated T cells exhibited antigen-specific interferon-gamma (IFN-γ) secretion and lysed cCD20+ targets. In a first-in-canine study, autologous cCD20-ζ CAR T cells were administered to a dog with relapsed B cell lymphoma. Treatment was well tolerated and led to a modest, but transient, antitumor activity, suggesting that stable CAR expression will be necessary for durable clinical remissions. Our study establishes the methodologies necessary to evaluate CAR T cell therapy in dogs with spontaneous malignancies and lays the foundation for use of outbred canine cancer patients to evaluate the safety and efficacy of next-generation CAR therapies and their optimization prior to translation into humans.
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Antigens, CD20/immunology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Cell Line, Tumor ; Cyclophosphamide/therapeutic use ; Dogs ; Doxorubicin/therapeutic use ; Electroporation ; Gene Expression ; Humans ; Immunotherapy, Adoptive/methods ; Interleukin-2/pharmacology ; Interleukins/pharmacology ; Lymphocyte Activation/immunology ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/immunology ; Lymphoma, B-Cell/metabolism ; Lymphoma, B-Cell/therapy ; Mice ; Prednisone/therapeutic use ; RNA, Messenger ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Transfection ; Treatment Outcome ; Vincristine/therapeutic use
Chemical Substances	Antigens, CD20 ; Interleukin-2 ; Interleukins ; RNA, Messenger ; Receptors, Antigen, T-Cell ; Vincristine (5J49Q6B70F) ; Doxorubicin (80168379AG) ; Cyclophosphamide (8N3DW7272P) ; interleukin-21 (MKM3CA6LT1) ; Prednisone (VB0R961HZT)
Language	English
Publishing date	2016-07-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1038/mt.2016.146
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Zs.A 5640: Show issues

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Article ; Online: Redundant catecholamine signaling consolidates fear memory via phospholipase C.

Ouyang, Ming / Young, Matthew B / Lestini, Melissa M / Schutsky, Keith / Thomas, Steven A

The Journal of neuroscience : the official journal of the Society for Neuroscience

2012 Volume 32, Issue 6, Page(s) 1932–1941

Abstract: Memories for emotionally arousing experiences are typically vivid and persistent. The recurrent, intrusive memories of traumatic events in post-traumatic stress disorder (PTSD) are an extreme example. Stress-responsive neurotransmitters released during ... ...

Abstract	Memories for emotionally arousing experiences are typically vivid and persistent. The recurrent, intrusive memories of traumatic events in post-traumatic stress disorder (PTSD) are an extreme example. Stress-responsive neurotransmitters released during emotional arousal are proposed to enhance the consolidation of fear memory. These transmitters may include norepinephrine and epinephrine (NE/E) because stimulating β-adrenergic receptors shortly after training can enhance memory consolidation. However, mice lacking NE/E acquire and consolidate fear memory normally. Here, we show by using pharmacologic and genetic manipulations in mice and rats that NE/E are not essential for classical fear memory consolidation because signaling by the β(2)-adrenergic receptor is redundant with signaling by dopamine at the D(5)-dopaminergic receptor. The intracellular signaling that is stimulated by these receptors to promote consolidation uses distinct G proteins to redundantly activate phospholipase C. The results support recent evidence indicating that blocking β-adrenergic receptors alone shortly after trauma may not be sufficient to prevent PTSD.
MeSH term(s)	Animals ; Brain Injuries/enzymology ; Brain Injuries/metabolism ; Brain Injuries/psychology ; Dopamine/physiology ; Epinephrine/deficiency ; Epinephrine/physiology ; Fear/physiology ; Fear/psychology ; Female ; Memory/physiology ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Norepinephrine/deficiency ; Norepinephrine/physiology ; Rats ; Rats, Inbred F344 ; Receptors, Adrenergic, beta-2/physiology ; Receptors, Dopamine D5/physiology ; Signal Transduction/physiology ; Type C Phospholipases/physiology
Chemical Substances	Receptors, Adrenergic, beta-2 ; Receptors, Dopamine D5 (137750-35-7) ; Type C Phospholipases (EC 3.1.4.-) ; Dopamine (VTD58H1Z2X) ; Norepinephrine (X4W3ENH1CV) ; Epinephrine (YKH834O4BH)
Language	English
Publishing date	2012-02-09
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.5231-11.2012
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Zs.A 1668: Show issues

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Article ; Online: Stress and glucocorticoids impair memory retrieval via β2-adrenergic, Gi/o-coupled suppression of cAMP signaling.

Schutsky, Keith / Ouyang, Ming / Castelino, Christina B / Zhang, Lei / Thomas, Steven A

The Journal of neuroscience : the official journal of the Society for Neuroscience

2011 Volume 31, Issue 40, Page(s) 14172–14181

Abstract: Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/ ...

Abstract	Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating β(1)-adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, β(1), and cAMP signaling is transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs before testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of β(2) (but not β(1))-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and β(2) agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by G(i/o)-coupled receptors. In hippocampal slices, β(2) signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by β(1) signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic β(2) agonists or glucocorticoids. These results demonstrate that the β(2) receptor can be a critical effector of acute stress, and that β(1) and β(2) receptors can have quite distinct roles in CNS signaling and cognition.
MeSH term(s)	Animals ; Cyclic AMP/antagonists & inhibitors ; Cyclic AMP/physiology ; Fear/drug effects ; Fear/physiology ; Fear/psychology ; Female ; GTP-Binding Protein alpha Subunits, Gi-Go/antagonists & inhibitors ; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism ; GTP-Binding Protein alpha Subunits, Gi-Go/physiology ; Glucocorticoids/toxicity ; Male ; Memory/physiology ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Knockout ; Mice, Transgenic ; Pertussis Toxin/pharmacology ; Rats ; Rats, Inbred F344 ; Receptors, Adrenergic, beta-2/physiology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Stress, Psychological/metabolism ; Stress, Psychological/psychology
Chemical Substances	Glucocorticoids ; Receptors, Adrenergic, beta-2 ; Cyclic AMP (E0399OZS9N) ; Pertussis Toxin (EC 2.4.2.31) ; GTP-Binding Protein alpha Subunits, Gi-Go (EC 3.6.5.1)
Language	English
Publishing date	2011-10-05
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2122-11.2011
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Zs.A 1668: Show issues

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Article ; Online: Intramuscular inoculation of mice with the live-attenuated recombinant rabies virus TriGAS results in a transient infection of the draining lymph nodes and a robust, long-lasting protective immune response against rabies.

Schutsky, Keith / Curtis, Dana / Bongiorno, Emily K / Barkhouse, Darryll A / Kean, Rhonda B / Dietzschold, Bernhard / Hooper, D Craig / Faber, Milosz

Journal of virology

2012 Volume 87, Issue 3, Page(s) 1834–1841

Abstract: A single intramuscular application of the live but not UV-inactivated recombinant rabies virus (RABV) variant TriGAS in mice induces the robust and sustained production of RABV-neutralizing antibodies that correlate with long-term protection against ... ...

Abstract	A single intramuscular application of the live but not UV-inactivated recombinant rabies virus (RABV) variant TriGAS in mice induces the robust and sustained production of RABV-neutralizing antibodies that correlate with long-term protection against challenge with an otherwise lethal dose of the wild-type RABV. To obtain insight into the mechanism by which live TriGAS induces long-lasting protective immunity, quantitative PCR (qPCR) analysis of muscle tissue, draining lymph nodes, spleen, spinal cord, and brain at different times after TriGAS inoculation revealed the presence of significant copy numbers of RABV-specific RNA in muscle, lymph node, and to a lesser extent, spleen for several days postinfection. Notably, no significant amounts of RABV RNA were detected in brain or spinal cord at any time after TriGAS inoculation. Differential qPCR analysis revealed that the RABV-specific RNA detected in muscle is predominantly genomic RNA, whereas RABV RNA detected in draining lymph nodes is predominantly mRNA. Comparison of genomic RNA and mRNA obtained from isolated lymph node cells showed the highest mRNA-to-genomic-RNA ratios in B cells and dendritic cells (DCs), suggesting that these cells represent the major cell population that is infected in the lymph node. Since RABV RNA declined to undetectable levels by 14 days postinoculation of TriGAS, we speculate that a transient infection of DCs with TriGAS may be highly immunostimulatory through mechanisms that enhance antigen presentation. Our results support the superior efficacy and safety of TriGAS and advocate for its utility as a vaccine.
MeSH term(s)	Animals ; B-Lymphocytes/virology ; Brain/pathology ; Brain/virology ; Dendritic Cells/virology ; Female ; Injections, Intramuscular ; Lymph Nodes/immunology ; Lymph Nodes/pathology ; Lymph Nodes/virology ; Mice ; Muscles/pathology ; Muscles/virology ; RNA, Viral/analysis ; RNA, Viral/genetics ; Rabies/prevention & control ; Rabies/virology ; Rabies Vaccines/administration & dosage ; Rabies Vaccines/immunology ; Rabies virus/immunology ; Rabies virus/pathogenicity ; Real-Time Polymerase Chain Reaction ; Spinal Cord/pathology ; Spinal Cord/virology ; Spleen/pathology ; Spleen/virology ; Vaccines, Attenuated/administration & dosage ; Vaccines, Attenuated/immunology
Chemical Substances	RNA, Viral ; Rabies Vaccines ; Vaccines, Attenuated
Language	English
Publishing date	2012-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.02589-12
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Article: Combined 90Yttrium-DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft.

Gold, David V / Modrak, David E / Schutsky, Keith / Cardillo, Thomas M

International journal of cancer

2004 Volume 109, Issue 4, Page(s) 618–626

Abstract: We have examined the application of (90)Y-DOTA-cPAM4, anti-MUC1 IgG, in combination with the front-line drug gemcitabine as a potential therapeutic for pancreatic cancer. Athymic nude mice bearing CaPan1 human pancreatic cancer xenografts were ... ...

Abstract	We have examined the application of (90)Y-DOTA-cPAM4, anti-MUC1 IgG, in combination with the front-line drug gemcitabine as a potential therapeutic for pancreatic cancer. Athymic nude mice bearing CaPan1 human pancreatic cancer xenografts were administered 2 mg of gemcitabine on days 0, 3, 6, 9 and 12 with concurrent (90)Y-DOTA-cPAM4 (100 microCi) provided on day 0. A second group of mice received a second cycle of treatment 5 weeks after the start of the first cycle. Control groups of mice included those that received either treatment arm alone, the combined modality treatment employing a nontargeting control antibody (hLL2, anti-B-cell lymphoma) and a final group that was left untreated. Gemcitabine administered as a single agent provided no antitumor effect. A single cycle of the combined (90)Y-DOTA-cPAM4 and gemcitabine treatment provided greater inhibition of tumor growth than was observed for any of the other treatment procedures. Tumor growth was delayed for a period of 7 weeks. Two cycles of gemcitabine with concomitant (90)Y-DOTA-cPAM4 yielded significant tumor regression and increased median survival to 21 weeks vs. 12 weeks for mice receiving a single cycle of therapy (p<0.024). Median tumor volume doubling-times were 18 weeks in mice treated with 2-cycles of therapy vs. 7 weeks in mice given only 1-cycle (p<0.001), and 3.5 weeks for the group that received 2-cycles of gemcitabine concomitant with equitoxic nontargeting (90)Y-DOTA-hLL2 (p<0.001). These data suggest that addition of (90)Y-DOTA-cPAM4 RAIT to a gemcitabine treatment regimen may provide enhanced antitumor efficacy for the treatment of pancreatic cancer.
MeSH term(s)	Adenocarcinoma/therapy ; Animals ; Antibodies, Monoclonal/therapeutic use ; Antimetabolites, Antineoplastic/therapeutic use ; Body Weight ; Combined Modality Therapy ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/therapeutic use ; Female ; Heterocyclic Compounds/therapeutic use ; Humans ; Maximum Tolerated Dose ; Mice ; Mice, Nude ; Neoplasms, Experimental/therapy ; Organometallic Compounds/therapeutic use ; Pancreatic Neoplasms/therapy ; Radiation-Sensitizing Agents/therapeutic use ; Radioimmunotherapy ; Survival Rate ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Yttrium Radioisotopes/therapeutic use
Chemical Substances	Antibodies, Monoclonal ; Antimetabolites, Antineoplastic ; Heterocyclic Compounds ; Organometallic Compounds ; Radiation-Sensitizing Agents ; Yttrium Radioisotopes ; yttrium(III)-1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid ; Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R)
Language	English
Publishing date	2004-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.20004
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