The Experts below are selected from a list of 1752 Experts worldwide ranked by ideXlab platform
Kevin Burgess - One of the best experts on this subject based on the ideXlab platform.
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targeted maytansinoid conjugate improves therapeutic index for metastatic breast cancer cells
Bioconjugate Chemistry, 2018Co-Authors: Zhengyang Jiang, Nathan Fishkin, Zhen Yang, Kevin BurgessAbstract:This study was undertaken to target cell surface Receptors other than the ones typically associated with breast cancer {estrogen Receptor (ER), progesterone Receptor (PR), and human epidermal growth factor Receptor 2 (HER2)}. It was also launched to use small molecules other than those most widely used for active targeting in general ( e.g. folate and carbonic anhydrase IX ligands). Specifically, the focus of this study was on unique small molecules that bind the TrkC Receptor, which is overexpressed in metastatic breast cancer. A conjugate (1) of a TrkC-targeting small molecule and the highly cytotoxic warhead, DM4 (a maytansinoid), was prepared. Cellular studies featuring TrkC+ and TrkC- human breast cells indicated this conjugate might have a better therapeutic effect than DM4 alone. It emerged that the conjugate 1 was very efficacious in vivo, completely ablating orthotopic 4T1 breast tumor in one case and dramatically reducing the tumor size in four other mice. Throughout, no significant weight loss or obvious neurotoxic effects were observed in the animals tested.
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Targeted Maytansinoid Conjugate Improves Therapeutic Index for Metastatic Breast Cancer Cells
2018Co-Authors: Zhengyang Jiang, Nathan Fishkin, Zhen Yang, Kevin BurgessAbstract:This study was undertaken to target cell surface Receptors other than the ones typically associated with breast cancer {estrogen Receptor (ER), progesterone Receptor (PR), and human epidermal growth factor Receptor 2 (HER2)}. It was also launched to use small molecules other than those most widely used for active targeting in general (e.g. folate and carbonic anhydrase IX ligands). Specifically, the focus of this study was on unique small molecules that bind the TrkC Receptor, which is overexpressed in metastatic breast cancer. A conjugate (1) of a TrkC-targeting small molecule and the highly cytotoxic warhead, DM4 (a maytansinoid), was prepared. Cellular studies featuring TrkC+ and TrkC– human breast cells indicated this conjugate might have a better therapeutic effect than DM4 alone. It emerged that the conjugate 1 was very efficacious in vivo, completely ablating orthotopic 4T1 breast tumor in one case and dramatically reducing the tumor size in four other mice. Throughout, no significant weight loss or obvious neurotoxic effects were observed in the animals tested
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Double-Targeting Using a TrkC Ligand Conjugated to Dipyrrometheneboron Difluoride (BODIPY) Based Photodynamic Therapy (PDT) Agent
2016Co-Authors: Anyanee Kamkaew, Kevin BurgessAbstract:A molecule 1 (IY-IY-PDT) was designed to contain a fragment (IY-IY) that targets the TrkC Receptor and a photosensitizer that acts as an agent for photodynamic therapy (PDT). Molecule 1 had submicromolar photocytotoxicities to cells that were engineered to stably express TrkC (NIH3T3-TrkC) or that naturally express high levels of TrkC (SY5Y neuroblastoma lines). Control experiments showed that 1 is not cytotoxic in the dark and has significantly less photocytotoxicity toward cells that do not express TrkC (NIH3T3-WT). Other controls featuring a similar agent 2 (YI-YI-PDT), which is identical and isomeric with 1 except that the targeting region is scrambled (a YI-YI motif, see text), showed that 1 is considerably more photocytotoxic than 2 on TrkC+ cells. Imaging live TrkC+ cells after treatment with a fluorescent agent 1 (IY-IY-PDT) proved that 1 permeates into TrkC+ cells and is localized in the lysosomes. This observation indirectly indicates that agent 1 enters the cells via the TrkC Receptor. Consistent with this, the dose-dependent PDT effects of 1 can be competitively reduced by the natural TrkC ligand, neurotrophin NT3
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bivalent diketopiperazine based tropomysin Receptor kinase c TrkC antagonists
Journal of Medicinal Chemistry, 2010Co-Authors: Jing Liu, Fouad Brahimi, Uri H Saragovi, Kevin BurgessAbstract:Bivalent molecules containing two β-turn mimics with side chains that correspond to hot-spots on the neurotrophin NT-3 were prepared. Binding assays showed the mimetics to be selective TrkC ligands, and biological assays showed one mimetic to be an antagonist of the TrkC Receptor.
V R King - One of the best experts on this subject based on the ideXlab platform.
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changes in truncated trkb and p75 Receptor expression in the rat spinal cord following spinal cord hemisection and spinal cord hemisection plus neurotrophin treatment
Experimental Neurology, 2000Co-Authors: V R King, Elizabeth J Bradbury, Stephen B. Mcmahon, John V PriestleyAbstract:Although numerous studies have examined the effects of neurotrophin treatment following spinal cord injury, few have examined the changes that occur in the neurotrophin Receptors following either such damage or neurotrophin treatment. To determine what changes occur in neurotrophin Receptor expression following spinal cord damage, adult rats received a midthoracic spinal cord hemisection alone or in combination with intrathecal application of brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3). Using immunohistochemical and in situ hybridization techniques, p75, trkA, trkB, and TrkC Receptor expression was examined throughout the spinal cord. Results showed that trkA, full-length trkB, and TrkC Receptors were not present in the lesion site but had a normal expression pattern in uninjured parts of the spinal cord. In contrast, p75 Receptor expression occurred on Schwann cells throughout the lesion site. BDNF and NT-3 (but not saline) applied to the lesion site increased this expression. In addition, the truncated trkB Receptor was expressed in the border between the lesion and intact spinal cord. Truncated trkB Receptor expression was also increased throughout the white matter ipsilateral to the lesion and BDNF (but not NT-3 or saline) prevented this increase. The study is the first to show changes in truncated trkB Receptor expression that extend beyond the site of a spinal cord lesion and is one of the first to show that BDNF and NT-3 affect Schwann cells and/or p75 expression following spinal cord damage. These results indicate that changes in neurotrophin Receptor expression following spinal cord injury could influence the availability of neurotrophins at the lesion site. In addition, neurotrophins may affect their own availability to damaged neurons by altering the expression of the p75 and truncated trkB Receptor.
Lino Tessarollo - One of the best experts on this subject based on the ideXlab platform.
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A kinase-deficient TrkC Receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin.
Journal of Cell Biology, 2006Co-Authors: Pedro F. Esteban, Paul A. Randazzo, Hye-young Yoon, Jodi Becker, Susan G. Dorsey, Paola Caprari, Mary Ellen Palko, H. Uri Saragovi, Vincenzo Coppola, Lino TessarolloAbstract:Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk Receptors and the p75 neurotrophin Receptor. Truncated Trk Receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated Receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1–tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 Receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.
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evidence for a role of truncated TrkC Receptor isoforms in mouse development
The Journal of Neuroscience, 1999Co-Authors: Mary Ellen Palko, Vincenzo Coppola, Lino TessarolloAbstract:The TrkC locus encodes several Receptors for neurotrophin-3, including the well studied full-length tyrosine kinase isoform, in addition to Receptor isoforms lacking the kinase active domain. TrkC Receptors are widely expressed throughout mouse development in many different organs. To investigate the function of truncated Receptors in vivo and to identify cell types that are biologically responsive to this gene product, we have overexpressed a physiological truncated TrkC isoform in the mouse. Mice overexpressing this Receptor develop to term but die in the first postnatal days. High levels of transgene expression result in severe developmental defects in the peripheral nervous system and in the heart. The severity of neuronal losses observed in these animals suggests that truncated Receptors may act by sequestering neurotrophin, thus, closely relating this mouse model to the neurotrophin-3-deficient one. Lower levels of exogenous truncated Receptor in transgenic mice result in a more modest phenotype and, in some neuronal populations, do not cause neural deficits. Taken together, these data suggest that truncated TrkC Receptor isoforms may have modulatory functions in development.
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targeted deletion of all isoforms of the TrkC gene suggests the use of alternate Receptors by its ligand neurotrophin 3 in neuronal development and implicates TrkC in normal cardiogenesis
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Lino Tessarollo, Mary Ellen Palko, Michael J. Donovan, Barbara L. Hempstead, Pantelis Tsoulfas, Janet Blairflynn, Luis F ParadaAbstract:We have generated null mutant mice that lack expression of all isoforms encoded by the TrkC locus. These mice display a behavioral phenotype characterized by a loss of proprioceptive neurons. Neuronal counts of sensory ganglia in the TrkC mutant mice reveal less severe losses than those in NT-3 null mutant mice, strongly suggesting that NT-3, in vivo, may signal through Receptors other than TrkC. Mice lacking either NT-3 or all TrkC Receptor isoforms die in the early postnatal period. Histological examination of TrkC-deficient mice reveals severe cardiac defects such as atrial and ventricular septal defects, and valvular defects including pulmonic stenosis. Formation of these structures during development is dependent on cardiac neural crest function. The similarities in cardiac defects observed in the TrkC and NT-3 null mutant mice indicate that the TrkC Receptor mediates most NT-3 effects on the cardiac neural crest.
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Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development.
Nature genetics, 1996Co-Authors: Michael J. Donovan, Lino Tessarollo, Rebecca T. Hahn, Barbara L. HempsteadAbstract:Neurotrophin 3 (Nt3) is one of five neurotrophin growth factors which shape the development of the nervous system by regulating neuronal survival and differentiation. Peripheral neuronal subpopulations expressing the TrkC Receptor tyrosine kinase respond to Nt3 with enhanced survival, mitogenesis or cell migration1–3 and these neurons are lost in homozygous Nt3 null (−/−) mutant mice4–7. The unexplained perinatal lethality in the Nt3−/− mice, however, suggests a wider function for this neurotrophin. Here we report that Nt3 is essential for the normal development of atria, ventricles, and cardiac outflow tracts. Histological and echocardiographic image analysis of Nt3−/− animals reveal severe cardiovascular abnormalities including atrial and ventricular septal defects, and tetralogy of Fallot, resembling some of the most common congenital malformations in humans. The observed defects are consistent with abnormalities in the survival and/or migration of cardiac neural crest early in embryogenesis8 and establish an essential role for neurotrophin 3 in regulating the development of the mammalian heart.
John V Priestley - One of the best experts on this subject based on the ideXlab platform.
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changes in truncated trkb and p75 Receptor expression in the rat spinal cord following spinal cord hemisection and spinal cord hemisection plus neurotrophin treatment
Experimental Neurology, 2000Co-Authors: V R King, Elizabeth J Bradbury, Stephen B. Mcmahon, John V PriestleyAbstract:Although numerous studies have examined the effects of neurotrophin treatment following spinal cord injury, few have examined the changes that occur in the neurotrophin Receptors following either such damage or neurotrophin treatment. To determine what changes occur in neurotrophin Receptor expression following spinal cord damage, adult rats received a midthoracic spinal cord hemisection alone or in combination with intrathecal application of brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3). Using immunohistochemical and in situ hybridization techniques, p75, trkA, trkB, and TrkC Receptor expression was examined throughout the spinal cord. Results showed that trkA, full-length trkB, and TrkC Receptors were not present in the lesion site but had a normal expression pattern in uninjured parts of the spinal cord. In contrast, p75 Receptor expression occurred on Schwann cells throughout the lesion site. BDNF and NT-3 (but not saline) applied to the lesion site increased this expression. In addition, the truncated trkB Receptor was expressed in the border between the lesion and intact spinal cord. Truncated trkB Receptor expression was also increased throughout the white matter ipsilateral to the lesion and BDNF (but not NT-3 or saline) prevented this increase. The study is the first to show changes in truncated trkB Receptor expression that extend beyond the site of a spinal cord lesion and is one of the first to show that BDNF and NT-3 affect Schwann cells and/or p75 expression following spinal cord damage. These results indicate that changes in neurotrophin Receptor expression following spinal cord injury could influence the availability of neurotrophins at the lesion site. In addition, neurotrophins may affect their own availability to damaged neurons by altering the expression of the p75 and truncated trkB Receptor.
Frederic Antonio Carvalho - One of the best experts on this subject based on the ideXlab platform.
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c jun p38mapk asic3 pathways specifically activated by nerve growth factor through trka are crucial for mechanical allodynia development
Pain, 2020Co-Authors: Tanguy Chaumette, Wassim Legha, Lauriane Delay, Julie Barbier, Ludivine Boudieu, Youssef Aissouni, Mathieu Meleine, Amandine Lashermes, Sophie Antraigue, Frederic Antonio CarvalhoAbstract:Mechanical allodynia is a cardinal sign of several inflammatory pain disorders where nerve growth factor, a prototypic neurotrophin, plays a crucial role by binding to TrkA Receptors. Here, we took the advantage of our generated knock-in mouse model expressing a chimeric TrkA/TrkC Receptor that seems to not specifically develop mechanical allodynia after inflammation, to identify the TrkA downstream pathways involved in this phenomenon. We confirmed and extended that disrupting TrkA-specific pathways leads to a specific deficit in mechanical hypersensitivity development after somatic (systemic nerve growth factor administration and paw incision) and, to a lesser extent, visceral injuries. Despite a deficit in thin, mainly peptidergic, fibre innervation in TrkAC mice, thermal hyperalgesia development was not different from WT mice. Inflammatory reaction (oedema, IL-6 content), pain behaviours after intraplantar capsaicin, as well as TRPV1 calcium imaging response of dorsal root ganglion neurons were similar between TrkAC and WT mice. This deficiency in mechanical allodynia development in TrkAC mice is likely due to the alteration of the expression of different TrkA transduction pathways (ie, Akt, p38 MAPK, and c-Jun) especially p38 MAPK, in the dorsal root ganglion cell bodies, ultimately leading to an alteration of at least, ASIC3 channel overexpression, known to participate in nociceptor mechanosensory function.
