TY - JOUR AB - Motor cortex (M1) exhibits a rich repertoire of neuronal activities to support the generation of complex movements. Although recent neuronal-network models capture many qualitative aspects of M1 dynamics, they can generate only a few distinct movements. Additionally, it is unclear how M1 efficiently controls movements over a wide range of shapes and speeds. We demonstrate that modulation of neuronal input–output gains in recurrent neuronal-network models with a fixed architecture can dramatically reorganize neuronal activity and thus downstream muscle outputs. Consistent with the observation of diffuse neuromodulatory projections to M1, a relatively small number of modulatory control units provide sufficient flexibility to adjust high-dimensional network activity using a simple reward-based learning rule. Furthermore, it is possible to assemble novel movements from previously learned primitives, and one can separately change movement speed while preserving movement shape. Our results provide a new perspective on the role of modulatory systems in controlling recurrent cortical activity. AU - Stroud, Jake P. AU - Porter, Mason A. AU - Hennequin, Guillaume AU - Vogels, Tim P ID - 8073 IS - 12 JF - Nature Neuroscience SN - 1097-6256 TI - Motor primitives in space and time via targeted gain modulation in cortical networks VL - 21 ER - TY - JOUR AU - Fazekas-Singer, Judit AU - Singer, Josef AU - Ilieva, Kristina M. AU - Matz, Miroslawa AU - Herrmann, Ina AU - Spillner, Edzard AU - Karagiannis, Sophia N. AU - Jensen-Jarolim, Erika ID - 8231 IS - 3 JF - Journal of Allergy and Clinical Immunology SN - 0091-6749 TI - AllergoOncology: Generating a canine anticancer IgE against the epidermal growth factor receptor VL - 142 ER - TY - JOUR AB - Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as ≥2.3-fold higher accumulation of FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1) poor conservation of target expression in xenografts and (2) unfavorable pharmacokinetics of FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using FE@SUPPY. AU - Balber, T. AU - Singer, Judit AU - Berroterán-Infante, N. AU - Dumanic, M. AU - Fetty, L. AU - Fazekas-Singer, J. AU - Vraka, C. AU - Nics, L. AU - Bergmann, M. AU - Pallitsch, K. AU - Spreitzer, H. AU - Wadsak, W. AU - Hacker, M. AU - Jensen-Jarolim, E. AU - Viernstein, H. AU - Mitterhauser, M. ID - 8234 JF - Contrast Media & Molecular Imaging SN - 1555-4309 TI - Preclinical in vitro and in vivo evaluation of [18F]FE@SUPPY for cancer PET imaging: Limitations of a xenograft model for colorectal cancer VL - 2018 ER - TY - JOUR AB - Anti-epidermal growth factor receptor (EGFR) antibody therapy is used in EGFR expressing cancers including lung, colon, head and neck, and bladder cancers, however results have been modest. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate which is activated by NIR light. NIR-PIT is in clinical trials in patients with recurrent head and neck cancers using cetuximab-IR700 as the conjugate. However, its use has otherwise been restricted to mouse models. This is an effort to explore larger animal models with NIR-PIT. We describe the use of a recombinant canine anti-EGFR monoclonal antibody (mAb), can225IgG, conjugated to the photo-absorber, IR700DX, in three EGFR expressing canine transitional cell carcinoma (TCC) cell lines as a prelude to possible canine clinical studies. Can225-IR700 conjugate showed specific binding and cell-specific killing after NIR-PIT on EGFR expressing cells in vitro. In the in vivo study, can225-IR700 conjugate demonstrated accumulation of the fluorescent conjugate with high tumor-to-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of can225-IR700 i.v. only; (3) NIR light exposure only; (4) 100 μg of can225-IR700 i.v., NIR light exposure. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.001 vs. other groups) in the treatment groups. In conclusion, NIR-PIT with can225-IR700 is a promising treatment for canine EGFR-expressing cancers, including invasive transitional cell carcinoma in pet dogs, that could provide a pathway to translation to humans. AU - Nagaya, Tadanobu AU - Okuyama, Shuhei AU - Ogata, Fusa AU - Maruoka, Yasuhiro AU - Knapp, Deborah W. AU - Karagiannis, Sophia N. AU - Fazekas-Singer, Judit AU - Choyke, Peter L. AU - LeBlanc, Amy K. AU - Jensen-Jarolim, Erika AU - Kobayashi, Hisataka ID - 8232 JF - Oncotarget TI - Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody VL - 9 ER - TY - JOUR AB - The M2a subtype of macrophages plays an important role in human immunoglobulin E (IgE-mediated allergies) and other Th2 type immune reactions. In contrast, very little is known about these cells in the dog. Here we describe an in vitro method to activate canine histiocytic DH82 cells and primary canine monocyte-derived macrophages (MDMs) toward the M2a macrophages using human cytokines. For a side-by-side comparison, we compared the canine cells to human MDMs, and the human monocytic cell line U937 activated towards M1 and M2a cells on the cellular and molecular level. In analogy to activated human M2a cells, canine M2a, differentiated from both DH82 and MDMs, showed an increase in CD206 surface receptor expression compared to M1. Interestingly, canine M2a, but not M1 derived from MDM, upregulated the high-affinity IgE receptor (FcεRI). Transcription levels of M2a-associated genes (IL10, CCL22, TGFβ, CD163) showed a diverse pattern between the human and dog species, whereas M1 genes (IDO1, CXCL11, IL6, TNF-α) were similarly upregulated in canine and human M1 cells (cell lines and MDMs). We suggest that our novel in vitro method will be suitable in comparative allergology studies focussing on macrophages. AU - Herrmann, Ina AU - Gotovina, Jelena AU - Fazekas-Singer, Judit AU - Fischer, Michael B. AU - Hufnagl, Karin AU - Bianchini, Rodolfo AU - Jensen-Jarolim, Erika ID - 8233 IS - 5 JF - Developmental & Comparative Immunology SN - 0145-305X TI - Canine macrophages can like human macrophages be in vitro activated toward the M2a subtype relevant in allergy VL - 82 ER -