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4 results on '"Loucks, F. Alexandra"'

1. Assessment of tumor hypoxia in spontaneous canine tumors after treatment with OMX, a novel H-NOX oxygen carrier, with [18F]FMISO PET/CT

Author

Choen, Sangkyung, Kent, Michael S, Loucks, F Alexandra, Winger, Jonathan A, and Zwingenberger, Allison L

Subjects
Veterinary Sciences, Agricultural, Veterinary and Food Sciences, Biological Sciences, Microbiology, Biomedical Imaging, Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Animals, Dogs, Misonidazole, Positron Emission Tomography Computed Tomography, Dog Diseases, Female, Tumor Hypoxia, Male, Neoplasms, Thiosemicarbazones, Coordination Complexes, Tumor hypoxia, Oxygen carrier, H-NOX protein, Canine tumors, [18F]Fluoromisonidazole, Positron emission tomography, Computed tomography, Therapy resistance, Non-invasive imaging, Biochemistry and Cell Biology, Veterinary sciences
Abstract

BackgroundHypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [18F]Fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [18F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors.ResultsThirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMRmax) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [18F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMRmax and HV in [18F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [18F]FMISO uptake and variable changes in TMRmax and HV.Conclusions[18F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMRmax and HV in [18F]FMISO PET imaging.

Published
2024

2. Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence

Author

Johnson, Carolyn M, Loucks, F Alexandra, Peckler, Hannah, Thomas, A Wren, Janak, Patricia H, and Wilbrecht, Linda

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Neurosciences, Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Afferent Pathways, Aging, Amygdala, Animals, Axons, Dendrites, Male, Mice, Neuronal Plasticity, Prefrontal Cortex, Pyramidal Cells, Sexual Maturation, Axonal bouton, Dendritic spine, Development, Two-photon microscopy, Structural plasticity, Pruning, Clinical Sciences, Cognitive Sciences, Biological psychology, Clinical and health psychology
Abstract

The adolescent transition from juvenile to adult is marked by anatomical and functional remodeling of brain networks. Currently, the cellular and synaptic level changes underlying the adolescent transition are only coarsely understood. Here, we use two-photon imaging to make time-lapse observations of long-range axons that innervate the frontal cortex in the living brain. We labeled cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) and imaged their axonal afferents to the dorsomedial prefrontal cortex (dmPFC). We also imaged the apical dendrites of dmPFC pyramidal neurons. Images were taken daily in separate cohorts of juvenile (P24-P28) and young adult mice (P64-P68), ages where we have previously discovered differences in dmPFC dependent decision-making. Dendritic spines were pruned across this peri-adolescent period, while BLA and OFC afferents followed alternate developmental trajectories. OFC boutons showed no decrease in density, but did show a decrease in daily bouton gain and loss with age. BLA axons showed an increase in both bouton density and daily bouton gain at the later age, suggesting a delayed window of enhanced plasticity. Our findings reveal projection specific maturation of synaptic structures within a single frontal region and suggest that stabilization is a more general characteristic of maturation than pruning.

Published
2016

3. Glutathione Binding to the Bcl-2 Homology-3 Domain Groove: A MOLECULAR BASIS FOR BCL-2 ANTIOXIDANT FUNCTION AT MITOCHONDRIA*

Author

Zimmermann, Angela K., Loucks, F. Alexandra, Schroeder, Emily K., Bouchard, Ron J., Tyler, Kenneth L., and Linseman, Daniel A.

Subjects
Neurons, Brain, Apoptosis, Oxidants, Glutathione, Article, Antioxidants, Mitochondria, Rats, Rats, Sprague-Dawley, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, Superoxides, Animals, biological phenomena, cell phenomena, and immunity, BH3 Interacting Domain Death Agonist Protein, Protein Binding
Abstract

Bcl-2 protects cells against mitochondrial oxidative stress and subsequent apoptosis. However, the mechanism underlying the antioxidant function of Bcl-2 is currently unknown. Recently, Bax and several Bcl-2 homology-3 domain (BH3)-only proteins (Bid, Puma, and Noxa) have been shown to induce a pro-oxidant state at mitochondria (1-4). Given the opposing effects of Bcl-2 and Bax/BH3-only proteins on the redox state of mitochondria, we hypothesized that the antioxidant function of Bcl-2 is antagonized by its interaction with the BH3 domains of pro-apoptotic family members. Here, we show that BH3 mimetics that bind to a hydrophobic surface (the BH3 groove) of Bcl-2 induce GSH-sensitive mitochondrial dysfunction and apoptosis in cerebellar granule neurons. BH3 mimetics displace a discrete mitochondrial GSH pool in neurons and suppress GSH transport into isolated rat brain mitochondria. Moreover, BH3 mimetics and the BH3-only protein, Bim, inhibit a novel interaction between Bcl-2 and GSH in vitro. These results suggest that Bcl-2 regulates an essential pool of mitochondrial GSH and that this regulation may depend upon Bcl-2 directly interacting with GSH via the BH3 groove. We conclude that this novel GSH binding property of Bcl-2 likely plays a central role in its antioxidant function at mitochondria.

Published
2007

4. Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons

Author

Le, Shoshona S., Loucks, F. Alexandra, Udo, Hiroshi, Richardson-Burns, Sarah, Phelps, Reid A., Bouchard, Ron J., Barth, Holger, Aktories, Klaus, Tyler, Kenneth L., Kandel, Eric R., Heidenreich, Kim A., and Linseman, Daniel A.

Subjects
rac1 GTP-Binding Protein, rho GTP-Binding Proteins, Integrins, Cell Survival, Proto-Oncogene Proteins c-jun, Bacterial Toxins, Apoptosis, Article, Rats, Sprague-Dawley, Bacterial Proteins, Cerebellum, Proto-Oncogene Proteins, Cell Adhesion, Animals, Cells, Cultured, Genes, Dominant, Neurons, Bcl-2-Like Protein 11, JNK Mitogen-Activated Protein Kinases, Cytochromes c, Membrane Proteins, Mitochondria, Rats, rac GTP-Binding Proteins, Enzyme Activation, Caspases, Apoptosis Regulatory Proteins, Carrier Proteins
Abstract

Rho GTPases are key transducers of integrin/extracellular matrix and growth factor signaling. Although integrin-mediated adhesion and trophic support suppress neuronal apoptosis, the role of Rho GTPases in neuronal survival is unclear. Here, we have identified Rac as a critical pro-survival GTPase in cerebellar granule neurons (CGNs) and elucidated a death pathway triggered by its inactivation. GTP-loading of Rac1 was maintained in CGNs by integrin-mediated (RGD-dependent) cell attachment and trophic support. Clostridium difficile toxin B (ToxB), a specific Rho family inhibitor, induced a selective caspase-mediated degradation of Rac1 without affecting RhoA or Cdc42 protein levels. Both ToxB and dominant-negative N17Rac1 elicited CGN apoptosis, characterized by cytochrome c release and activation of caspase-9 and -3, whereas dominant-negative N19RhoA or N17Cdc42 did not cause significant cell death. ToxB stimulated mitochondrial translocation and conformational activation of Bax, c-Jun activation, and induction of the BH3-only protein Bim. Similarly, c-Jun activation and Bim induction were observed with N17Rac1. A c-jun N-terminal protein kinase (JNK)/p38 inhibitor, SB203580, and a JNK-specific inhibitor, SP600125, significantly decreased ToxB-induced Bim expression and blunted each subsequent step of the apoptotic cascade. These results indicate that Rac acts downstream of integrins and growth factors to promote neuronal survival by repressing c-Jun/Bim-mediated mitochondrial apoptosis.

Published
2005

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