bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatosensory cortical excitability changes precede those in motor cortex during human motor learning
Authors: Ohashi Hiroki , Gribble Paul L. , Ostry David J. 
Published: August 2019

Motor learning is associated with plasticity in both motor and somatosensory cortex. It is known from animal studies that tetanic stimulation to each of these areas individually induces long-term potentiation in its counterpart. In this context it is possible that changes in motor cortex contribute to somatosensory change and that changes in somatosensory cortex are involved in changes in motor areas of the brain. It is also possible that learning-related plasticity occurs in these areas independently. To better understand the relative contribution to human motor learning of motor cortical and somatosensory plasticity, we assessed the time course of changes in primary somatosensory and motor cortex excitability during motor skill learning. Learning was assessed using a force production task in which a target force profile varied from one trial to the next. The excitability of primary somatosensory cortex was measured using somatosensory evoked potentials in response to median nerve stimulation. The excitability of primary motor cortex was measured using motor evoked potentials elicited by single-pulse transcranial magnetic stimulation. These two measures were interleaved with blocks of motor learning trials. We found that the earliest changes in cortical excitability during learning occurred in somatosensory cortical responses, and these changes preceded changes in motor cortical excitability. Changes in somatosensory evoked potentials were correlated with behavioral measures of learning. Changes in motor evoked potentials were not. These findings indicate that plasticity in somatosensory cortex occurs as a part of the earliest stages of motor learning, before changes in motor cortex are observed. NEW & NOTEWORTHY We tracked somatosensory and motor cortical excitability during motor skill acquisition. Changes in both motor cortical and somatosensory excitability were observed during learning; however, the earliest changes were in somatosensory cortex, not motor cortex. Moreover, the earliest changes in somatosensory cortical excitability predict the extent of subsequent learning; those in motor cortex do not. This is consistent with the idea that plasticity in somatosensory cortex coincides with the earliest stages of human motor learning.
Abstract 1007: Reactive oxygen species are essential for neurotensin receptors to regulate EGFR and HER2 transactivation
Authors: Moody Terry W. , Lee Lingaku , Jensen Robert T. 
Published: August 2019

Abstract
Neurotensin (NTS) is a 13 amino acid peptide which is present in many lung cancer cell lines (Moody et al., Life Sci 1985; 36: 1727). High expression of the NTS receptor 1 (R1) is associated with poor survival of non-small cell lung cancer (NSCLC) patients (Alfano et al., Clin Cancer Res 2010; 16: 4401). NTS stimulates but the NTSR1 antagonist SR48692 inhibits the proliferation of NSCLC cells (Moody et al., Life Sci 2014; 100: 25). NTSR1 regulates NSCLC proliferation by transactivation of the EGFR. The cellular signaling mechanisms of the NTSR1 were investigated using NSCLC cells. Using NCI-H838 or A549 cells, addition of NTS or NTS(8-13) but not NTS(1-8) increased tyrosine phosphorylation of P-EGFR, P-HER2 and P-ERK 4-, 3- and 2-fold, respectively. The increase in EGFR and HER2 transactivation caused by NTS addition to NSCLC cells was blocked by SR48692, gefitinib (EGFR tyrosine kinase inhibitor (TKI)), lapatinib (EGFR and HER2 TKI), N-acetyl cysteine ((NAC) is an antioxidant), tiron (reactive oxygen species (ROS) scavenger) or diphenyleneiodonium (DPI is an inhibitor of NOX and DUOX enzymes). NTS increased ROS in NSCLC cells which was inhibited by NAC, tiron or DPI. NTS or NTS(8-13) stimulate NSCLC colony growth but SR48692, gefitinib, lapatinib or DPI inhibit growth. The results indicate that the NTSR1 regulates in a ROS-dependent manner the formation of EGFR homodimers or EGFR-HER2 heterodimers in NSCLC cells.
Citation Format: Terry W. Moody, Lingaku Lee, Robert T. Jensen. Reactive oxygen species are essential for neurotensin receptors to regulate EGFR and HER2 transactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1007.
Abstract 1029: Metastatic cancer cells activate endothelial RhoA-ROCK pathway for trans-endothelial migration
Authors: Sajib Md Sanaullah , Zahra Fatema Tuz , Park Jee Hyun , Tullar Paul , Srivastava Sanjay K. , Bickel Ulrich , Mikelis Constantinos M 
Published: August 2019

Abstract
Metastasis is the process through which tumor cells disseminate from the primary tumor and colonize in distant parts of the body. Two of the steps in the metastatic process are the trans-migration of cancer cells through the endothelial lining of blood and lymphatic vessels, during entrance (intravasation) and exit (extravasation) from the vascular system. We and others have shown that the endothelial RhoA pathway plays important role in endothelial permeability. Translating these findings in the metastasis context we aim to explore the role of endothelial RhoA signaling pathway on cancer cell trans-endothelial migration and metastasis. In vitro, we have established a quantifiable, highly reproducible, transwell-based, two-cell co-culture model of trans-endothelial migration, where fluorescently-labeled cancer cells transmigrate through an endothelial monolayer. Pharmacological and molecular biology approaches were incorporated to dissect the role of endothelial RhoA signaling pathway. Primary and immortalized endothelial cells were used and cancer cells of both mouse and human origin were tested. In all cases, conditioned media from the cancer cells activated endothelial RhoA. Blockade of the RhoA pathway inhibited cancer cell trans-endothelial migration. In vivo, syngeneic and human cancer cell lines were tested in tail-vein and intra-cardiac models of experimental metastasis. We observed decreased lung metastatic nodules in endothelial-specific RhoA-deficient mice, compared to the littermate controls. Treatment with a clinically-relevant inhibitor of the RhoA pathway, Fasudil, also decreased the metastatic colonization of both human and cancer cells. The above findings demonstrate that the endothelial RhoA pathway has a pivotal role on cancer cell trans-endothelial migration.
Citation Format: Md Sanaullah Sajib, Fatema Tuz Zahra, Jee Hyun Park, Paul Tullar, Sanjay K. Srivastava, Ulrich Bickel, Constantinos M Mikelis. Metastatic cancer cells activate endothelial RhoA-ROCK pathway for trans-endothelial migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1029.
Abstract 1033: Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
Authors: Arner Emily N. , Cruz Victoria H. , Du Wenting , Brekken Rolf 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that higher levels of TBK1 mRNA are associated with poorer overall survival in human PDA patients and that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.
Citation Format: Emily N. Arner, Victoria H. Cruz, Wenting Du, Rolf Brekken. Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1033.
Abstract 1037: Axl is critical for pancreatic cancer progression and metastasis
Authors: Du Wenting , Huang Huocong , Toombs Jason , Wang Zhaoning , Hosein Abdel , Burton Natalie , Brekken Rolf A. 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer-related death in the US, has a high metastatic rate that is associated with persistent immune suppression. Axl, a member of the TAM (Tyro3, Axl, MerTK) receptor tyrosine kinase family, has been identified as a critical factor that drives metastasis and immune suppression in many cancer types. We have shown that pharmacological inhibition of Axl significantly reduces tumor progression and metastasis and improves response to chemotherapy in multiple preclinical PDAC models. Here we demonstrate that Axl-deficient PDAC bearing mice have longer median survival, smaller tumors, fewer metastases and higher sensitivity to chemotherapy (gemcitabine) compared to Axl wild-type (WT) PDAC mice. Furthermore, Axl-deficient PDAC displays a more differentiated histology and has a more inflammatory and active immune microenvironment. Single cell RNA sequencing of PDAC genetically engineered mouse models reveals that Axl is expressed highly in tumor cells that have a mesenchymal-like phenotype and Axl expression correlates with classic markers of mesenchymal tumor cells at the RNA and protein level. To investigate the importance of Axl on tumor cells, CRISPR-Cas9 was used to knockout Axl in PDAC cells. Human and murine Axl-deficient PDAC cells displayed a more differentiated (epithelial) phenotype in vitro including reduced migratory capacity compared to Axl WT parental cells. Orthotopic injection of Axl-deficient murine PDAC cells into Axl WT mice resulted in longer median survival and fewer metastases compared to WT mice injected with WT PDAC cells. However, Axl-deficient mice injected with WT PDAC cell injection showed similar median survival and metastases as WT mice injected with WT PDAC cells. These in vivo results indicate that Axl expression on tumor cells is critical for PDAC progression and metastasis. In vitro experiments using WT and Axl-deficient human PDAC cells show that Axl is required for TGFβ-mediated epithelial to mesenchymal transition, probably through regulating the expression of Smad2 and Smad4. Interesting, Axl depletion has no effect on the mRNA level of Smad2 and Smad4, but does decrease the protein level, indicating that Axl might be involved in post-translational regulation (e.g., protein stability) of canonical TGFβ signaling intermediates. In summary, our study demonstrates that Axl expressed by pancreatic cancer cells is critical to tumor cell plasticity, tumor progression and metastasis.
Citation Format: Wenting Du, Huocong Huang, Jason Toombs, Zhaoning Wang, Abdel Hosein, Natalie Burton, Rolf A. Brekken. Axl is critical for pancreatic cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1037.
Abstract 1041: Casein kinase 2 modulates epithelial mesenchymal transition through Helicobacter pylori CagA dependent pathway in gastric cancer cells
Authors: Lee SoDam , Hwang Bo Ram , Yun Jung Chang , Yu Byeong Min , Lee Yong Chan 
Published: August 2019

Abstract
Helicobacter pylori is the most important carcinogen in human gastric cancer. However, the pathogenic molecular mechanism which underlies the carcinogenesis in gastric cancer by H. pylori remains largely unknown. In this study, we understand that molecular biological mechanism related to gastric carcinogenesis by investigating the role of CK2 in EMT. Casein kinase 2 is a serine/threonine protein kinase and consists of two catalytic subunits (α or α’) and regulatory subunits (β). CK2 regulates many substrates and its involved in cell growth, proliferation, survival, angiogenesis, invasion. Epithelial-to-mesenchymal transition (EMT) is involved in many signaling pathways, but the key regulatory kinases in this process have not been clearly identified. In our previous study, we reported the cytotoxin-associated gene A (CagA) protein of H. pylori induces cell migration and invasion through increased CK2α activity in gastric epithelial cells. Although the role of CK2 catalytic subunits has remained largely uncharacterized, several studies have recently focused on regulator subunits in EMT.
Here, we analyzed the expression level of CK2α did not altered, whereas CK2β decreased in CagA-dependent pathway. Moreover, expression of ectopic CK2β was downregulated by CagA. This suggests that CagA negatively regulates the stability of CK2β protein. We examined the level of ubiquitinated CK2β were higher in HP60190 infected cells than in control cells. Thus, CK2β is degraded by the proteasomal machinery following CagA of H. pylori. In addition, CagA binds both CK2α and CK2β, which results in suppression of CK2β binding by infected HP60190, but does not suppress CK2α binding. Furthermore, downregulation of CK2β increased Snail such as CK2 target genes, EMT-related marker in H. pylori-infected gastric cancer cells. Therefore, the role of Snail regulated by CK2β should be considered when developing cancer therapeutic. Overall, CK2 tetramer subunits might control the function of CagA and EMT related genes, thereby regulating CagA-dependent pathology. Taken together, the results of the present study suggest that the CK2 regulatory subunit has diverse effect on CagA-dependent cellular processes. A pharmacological activator or activator of CK2β may have potential as a therapeutic agent for gastric cancer associated with CagA.
Citation Format: SoDam Lee, Bo Ram Hwang, Jung Chang Yun, Byeong Min Yu, Yong Chan Lee. Casein kinase 2 modulates epithelial mesenchymal transition through Helicobacter pylori CagA dependent pathway in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1041.
Abstract 1043: TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial-mesenchymal transition & metastasis in liver cancer
Authors: Wang Shen-Nien , Wang Li-Ting , Hsu Shih-Hsien 
Published: August 2019

Abstract
Metastasis is the main cause of cancer mortality. However, the triggering mechanisms and regulation of epithelial–mesenchymal transition (EMT) factors in the commitment of metastasis have not been well characterized. Spermatogenic Zip 1 (SPZ1) acts as a proto-oncogene and an upstream regulator of EMT during tumorigenesis. Here we report that the HIV-1 Tat-interacting protein 60 kDa (Tip60) acetyltransferase mediates acetylation at lysine residues of SPZ1 at positions 369 and 374, and of TWIST1 at positions 73 and 76, which are required for SPZ1–TWIST1 complex formation and cancer cell migration in vitro and in vivo. Ectopic SPZ1 and TWIST1 expression, but not that of TWIST1 alone, enhanced vascular endothelial growth factor (VEGF) expression via the recruitment of bromodomain-containing protein 4 (BRD4), thus enhancing RNA-Pol II-dependent transcription and inducing metastasis. Neutralization of VEGF using humanized monoclonal antibodies such as Avastin, effectively abrogated the EMT and oncogenesis induced by the acetylated SPZ1–TWIST1 complex. Our findings highlight the importance of acetylation signaling in the SPZ1–TWIST1–BRD4 axis in the mediation of EMT and its regulation during tumor initiation and metastasis.
Citation Format: Shen-Nien Wang, Li-Ting Wang, Shih-Hsien Hsu. TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial-mesenchymal transition & metastasis in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1043.
Abstract 105: MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells
Authors: Sanjiv Kumar , gad Helge , Rudd Sean G. , Mortusewicz Oliver , Stolz Ailine , Amaral Nuno , Brautigham Lars , Pudelko Linda , Kaldéren Christina , Jemth Ann-Sofie , Almlöf Ingrid , Visnes Torkild , Schultz Niklas , Boström Johan , Montano1 José Manuel Calderon , Hagenkort Anna , Groth Petra , Gokturk Camilla , Koolmeister Tobias , Wakchaure Prasad , Homan Evert , Altun Mikael , Ström Cecilia , Scobie Martin , Bastians Holger , Berglund Ulrika Warpman , Helleday Thomas 
Published: August 2019

Abstract
MTH1 prevents incorporation of oxidized deoxynucleoside triphosphates (e.g., 8-oxodGTP) into DNA. Earlier we demonstrated that MTH1 inhibitors TH588 and TH1579 possesses anti-cancer activity in various tumour types, while other structurally distinct MTH1 inhibitors failed to kill cancer cells or elevate the levels of oxidized nucleotides in DNA. In our current study, we found a novel function of MTH1 in mitosis, as it plays an important role in correct spindle assembly in cancer cells and progression through mitosis, and furthermore, we demonstrate MTH1 binds tubulin in vivo. We also observed that structurally distinct MTH1 inhibitors display differential abilities to break the MTH1 tubulin interaction, and also demonstrate that TH588 and TH1579 can directly inhibit tubulin polymerisation in vitro. Consistent with our results, we establish that TH588 and TH1579 kill cancer cells by a mitosis-dependent mechanism and implicate reactive oxygen species (ROS) accumulation and incorporation of oxidised nucleotides into DNA in this process. Furthermore, we found that non-cytotoxic MTH1 inhibitors can become cytotoxic and increase incorporation of oxidised nucleotides into DNA when they are combined with sub-therapeutic concentrations of mitotic inhibitors. In conclusion, MTH1 inhibitors killing cancer cells have a unique and complex mechanism of action: (1) causing a mitotic arrest, induced by targeting MTH1 which is required for mitotic progression, but also through direct inhibition of microtubule polymerisation, in-turn leading to an increase in ROS and likely 8-oxodGTP and (2) MTH1-dependent 8-oxodGTPase inhibitory activity causing incorporation of damaged nucleotides into DNA to kill cancer cells.
Citation Format: Kumar Sanjiv, Helge gad, Sean G. Rudd, Oliver Mortusewicz, Ailine Stolz, Nuno Amaral, Lars Brautigham, Linda Pudelko, Christina Kaldéren, Ann-Sofie Jemth, Ingrid Almlöf, Torkild Visnes, Niklas Schultz, Johan Boström, José Manuel Calderon Montano1, Anna Hagenkort, Petra Groth, Camilla Gokturk, Tobias Koolmeister, Prasad Wakchaure, Evert Homan, Mikael Altun, Cecilia Ström, Martin Scobie, Holger Bastians, Ulrika Warpman Berglund, Thomas Helleday. MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 105.
Abstract 1063: In vivo humanized immuno-oncologymodels for drug discovery
Authors: Cheng Jijun , Zhang Feifei , Long Yuan , Xu Wenhua , Chen Hongkui , Wen Danyi 
Published: August 2019

Abstract
Reliable translational, especially humanized mouse models are critical to evaluate efficacy of immuno-therapeutics. While transgenic humanized mice and human CD34+ HSC-reconstituted mice are often used, their human cellular or molecular immune components are limited or defective. Human peripheral blood monocytic cell (PBMC)-reconstitution in immunocompromised mice, although, is transient and limited in infiltrating xenografts, one can manipulate to delicately reconstitute tumor microenvironment with one type, human T cells, or a few types of human immune cells, dendritic and macrophages, from human PBMC, through either systemic reconstitution or local reconstitution. We found that optimized stable PBMC models, both CDX and PDX, can often meet needs of targeting by many developing IO antibody therapeutics, including bi-specifics, in comparison to other humanized models. In particular, for efficacy study and for the convenience of mouse trials, we arrayed panels of PDX models expressing PD-L1 at different levels, in lung, liver, endometrial and gastric cancers, and panels of MSI-H and/or dMMR positive PDX models in these cancer types. In aiding studies of efficacy and resistance, we establish clinically drug-resistant PDX models, such as those resistant to checkpoint antibody drugs. These models are valuable to evaluate efficacy not only for antibody agents but also for combinational therapies involving biotherapeutics such as oncolytic virus.
Citation Format: Jijun Cheng, Feifei Zhang, Yuan Long, Wenhua Xu, Hongkui Chen, Danyi Wen. In vivo humanized immuno-oncologymodels for drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1063.
Abstract 1068: How humanized mouse models could be useful for immuno-oncology research
Authors: Mirjolet Jean-Francois , Caradec Josselin , Duchamp Oliver , Bichat Francis , France Damien , Mignard Caroline , Viviani Fabrice 
Published: August 2019

Abstract
Immunotherapy is one of the most exiting recent breakthroughs in the field of cancer treatment. Different approaches are developed such as cancer vaccines, adoptive cellular immunotherapy or immune checkpoint blockade, and a number have been regulatory approved or are currently investigated in clinic. Effective immunity against cancer involves complex interaction between the tumor, the host and the environment. The assessment of cancer immunotherapy approaches in preclinical settings requires the use of appropriate animal models that sufficiently reflect the physiological situation in humans and that must be chosen carefully to address specific mechanisms of action. In light of evaluating the therapeutic potential of different immunomodulatory agents in mice xenografted with cancer cell lines or patient-derived xenografts, we developed multiple humanization strategies on different immuno-deficient mouse strains. Either human PBMCs, Hematopoietic Stem Cells (HSCs), or specific human immune cells such as Dendritic Cells (DCs), T cells, subset of T cells (e.g. gamma9 delta2 T cells) and NK cells were used, but also the combinations of immune subpopulations such as the co-transfer of autologous T cells and DCs. We will highlight some results of our therapeutic efficacy investigation and evaluation of novel immuno-oncology therapies eg. adoptive cell therapy, bispecific T-cell engager antibody, and vaccine immunomodulatory agents in such humanized mouse models, assessing survival, tumor growth and effects on tumors and immune cells by flow cytometry and immunohistochemistry analyses. All these different humanized models can permit to evidence significant antitumor efficacy of immunomodulatory agents in vivo and might help improve the success rate in clinical trials.
Citation Format: Jean-Francois Mirjolet, Josselin Caradec, Oliver Duchamp, Francis Bichat, Damien France, Caroline Mignard, Fabrice Viviani. How humanized mouse models could be useful for immuno-oncology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1068.