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Journal articles on the topic "Tans Model"
1
Timaxian, Colin, Christoph F. A. Vogel, Charlotte Orcel, et al. "Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer." Cancers 13, no. 11 (2021): 2584. http://dx.doi.org/10.3390/cancers13112584.
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Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2−/− animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2−/− TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2−/− TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2−/− TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects.
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Benson, Douglas D., Xianzhong Meng, David A. Fullerton, et al. "Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 302, no. 9 (2012): R1067—R1075. http://dx.doi.org/10.1152/ajpregu.00320.2011.
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The histologic presence of macrophages (tumor-associated macrophages, TAMs) and neutrophils (tumor-associated neutrophils, TANs) has been linked to poor clinical outcomes for solid tumors. The exact mechanism for this association with worsened prognosis is unclear. It has been theorized that TAMs are immunomodulated to an alternatively activated state and promote tumor progression. Similarly, TANs have been shown to promote angiogenesis and tumor detachment. TAMs and TANs were characterized for activation state and production of prometastatic mediators in an immunocompetent murine model of pancreatic adenocarcinoma. Specimens from liver metastases were evaluated by immunofluorescence and immunoblotting. TAMS have upregulated expression of CD206 and CD163 markers of alternative activation, (4.14 ± 0.55-fold and 7.36 ± 1.13-fold over control, respectively, P < 0.001) but do not have increased expression of classically activated macrophage markers CCR2 and CCR5. TAMs also express oncostatin M (OSM). We found that TANs, not TAMs, predominantly produce matrix metalloproteinase-9 (MMP-9) in this metastatic tumor microenvironment, while MMP-2 production is pan-tumoral. Moreover, increased expression of VEGF colocalized with TAMs as opposed to TANs. TAMs and TANs may act as distinct effector cells, with TAMs phenotypically exhibiting alternative activation and releasing OSM and VEGF. TANs are localized at the invasive front of the metastasis, where they colocalize with MMP-9. Improved understanding of these interactions may lead to targeted therapies for pancreas adenocarcinoma.
3
Zhou, Zhengjun, Pengcheng Wang, Rongqi Sun, et al. "Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3." Journal for ImmunoTherapy of Cancer 9, no. 3 (2021): e001946. http://dx.doi.org/10.1136/jitc-2020-001946.
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BackgroundTumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear.MethodsWe explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex immunofluorescent staining and tested their separate and combined effects on ICC in vitro and in vivo. We then investigated the mechanistic basis of the effects using PCR array, western blot analysis and ELISA experiments. Finally, we validated our results in a tissue microarray composed of primary tumor tissues from 359 patients with ICC.ResultsThe spatial distributions of TANs and TAMs were correlated with each other in patient-derived ICC samples. Interaction between TANs and TAMs enhanced the proliferation and invasion abilities of ICC cells in vitro and tumor progression in a mouse xenograft model of ICC. TANs and TAMs produced higher levels of oncostatin M and interleukin-11, respectively, in co-culture than in monoculture. Both of those cytokines activated STAT3 signaling in ICC cells. Knockdown of STAT3 abolished the protumor effect of TANs and TAMs on ICC. In tumor samples from patients with ICC, increased TAN and TAM levels were correlated with elevated p-STAT3 expression. All three of those factors were independent predictors of patient outcomes.ConclusionsTANs and TAMs interact to promote ICC progression by activating STAT3.
4
Han, Booyeon Julia, Luis I. Ruffolo, Katherine M. Jackson, et al. "Investigating the tumor-immune microenvironment in an autochthonous murine model of cholangiocarcinoma." Journal of Clinical Oncology 37, no. 8_suppl (2019): 53. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.53.
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53 Background: Cholangiocarcinoma (CCA) is the most common liver malignancy within the biliary tree with increasing incidence and poor survival. Although surgical resection can be curative, prognosis remains abysmal with high rates of unresectability and recurrence, and new systemic therapies are needed. CCA tumors are characterized by an abundant inflammatory immune cell infiltrate, yet little is known about the immune dynamics underlying the disease. Here, we present a preclinical murine model of CCA for identifying potential targets susceptible to immune-based therapies. Methods: Mice with targeted activation of KrasG12D and loss of p53 (Kras-p53-/-) in the liver were exposed to 5-Diethoxycarbonyl-1.4-dihydrocollidine for 4 weeks to induce spontaneous CCA tumorigenesis. Immunohistochemistry staining was performed for mouse and human CCA. Immune compartments (bone marrow, spleen, peripheral blood, tumor draining and non-draining lymph nodes, and CCA tumor) of mice were processed for CyTOF analysis. In vitro assays of isolated myeloid leukocytes were performed to demonstrate function. Results: Tumor associated neutrophils (TANs) and tumor associated macrophages (TAMs) were present in high levels in human CCA tumors and the murine model. CyTOF analysis demonstrated mobilization of TANs, TAMs, and CCR2+ inflammatory monocytes into the tumor. The checkpoint marker PD-1 was upregulated on CD8+ and CD4+ T cells and associated with PD-L1+ TANs, TAMs, monocytes, and dendritic cells. The immunosuppressive tumor microenvironment was also characterized by TAMs expressing IL-10, TGFβ, and arginase 1; regulatory B cells expressing IL-10 and TGFβ; and Gata3+ TH2 cells. Isolated myeloid leukocytes suppressed T cell proliferation and induced invasive migration. Conclusions: Kras-p53-/- mice developed CCA tumors histologically similar to human disease: the data portray immunosuppressive cells in the tumor microenvironment, a possible obstacle for an effective anti-tumor response. Understanding the immune dynamics of immunosuppressive populations within the tumor microenvironment will be key to mount a potent therapeutic response for durable remission and improved survival.
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Ashby, F. Gregory, and Matthew J. Crossley. "A Computational Model of How Cholinergic Interneurons Protect Striatal-dependent Learning." Journal of Cognitive Neuroscience 23, no. 6 (2011): 1549–66. http://dx.doi.org/10.1162/jocn.2010.21523.
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An essential component of skill acquisition is learning the environmental conditions in which that skill is relevant. This article proposes and tests a neurobiologically detailed theory of how such learning is mediated. The theory assumes that a key component of this learning is provided by the cholinergic interneurons in the striatum known as tonically active neurons (TANs). The TANs are assumed to exert a tonic inhibitory influence over cortical inputs to the striatum that prevents the execution of any striatal-dependent actions. The TANs learn to pause in rewarding environments, and this pause releases the striatal output neurons from this inhibitory effect, thereby facilitating the learning and expression of striatal-dependent behaviors. When rewards are no longer available, the TANs cease to pause, which protects striatal learning from decay. A computational version of this theory accounts for a variety of single-cell recording data and some classic behavioral phenomena, including fast reacquisition after extinction.
6
McAteer, Emily, and Simone Pulver. "The Corporate Boomerang: Shareholder Transnational Advocacy Networks Targeting Oil Companies in the Ecuadorian Amazon." Global Environmental Politics 9, no. 1 (2009): 1–30. http://dx.doi.org/10.1162/glep.2009.9.1.1.
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Transnational advocacy networks (TANs) targeting corporations differ from those targeting states in the strategies they employ, determinants of network effectiveness, and assessments of goal achievement. This article develops a corporate boomerang model to analyze the dynamics of corporate-focused TANs. The model is used to assess two case studies of corporate-focused TANs—targeting the US-based oil corporations Chevron and Burlington Resources—active in Ecuador's Amazon region. In both TANs, corporate shareholder activists played a central role in the networks. The comparison demonstrates that the success of the Burlington TAN relative to the Chevron TAN can be explained by differences in the cohesiveness of the two networks and in the vulnerability of the two targets.
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Beniwal, Angad, Saket Jain, Sumedh Shah, et al. "TAMI-38. TUMOR-ASSOCIATED NEUTROPHILS IN GLIOBLASTOMA PROMOTE THE PERIVASCULAR GLIOMA STEM-LIKE CELL NICHE VIA OSTEOPONTIN SECRETION." Neuro-Oncology 23, Supplement_6 (2021): vi206. http://dx.doi.org/10.1093/neuonc/noab196.822.
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Abstract Among clinical analyses, elevated neutrophil-lymphocyte ratio has been correlated with poor outcomes of glioblastoma patients independent of other prognostic factors. Additionally, our flow cytometric studies of primary patient samples found neutrophil percentage to be significantly higher in higher-grade glioma versus lower-grade glioma. Tumor-associated neutrophils (TANs) comprise less than 2% of the glioblastoma microenvironment. While TANs were initially considered passive bystanders due to their short-lived nature, investigation of TANs in other cancers revealed distinct pro-tumoral roles. Therefore, we transcriptomically characterized glioblastoma TANs and defined their oncologic effects. Transcriptomic analysis of patient-matched TANs versus peripheral blood neutrophils revealed that functionally quiescent circulating neutrophils infiltrate IDH1-wild type glioblastoma via leukotriene B4 chemoattraction, where tumor cells morphologically and transcriptomically activate them to become TANs. Single-cell RNA-sequencing of patient-matched TANs and peripheral blood neutrophils revealed a subset of tumor-activated neutrophils which adopt a pro-tumoral secretory phenotype, marked by activation of the IL-17 signaling pathway and high osteopontin production. Using immunofluorescence stains of primary patient glioblastoma sections, we demonstrated that activated, myeloperoxidase-positive TANs reside in the perivascular niche of glioblastoma in close proximity to glioblastoma stem-like cells (GSCs) and CD31-positive endothelial cells. Further analysis in culture demonstrated that TAN-secreted osteopontin drives the formation, self-renewal, and proliferation of GSC-containing neurospheres. These results were validated using a syngeneic stem cell-derived IDH1-wild type murine glioblastoma model in vivo. Thus, while TANs are rare in glioblastoma, their enrichment in the glioblastoma perivascular niche uniquely positions them to support the GSCs that are crucial to therapeutic resistance of GBM.
8
Vannitamby, Amanda, Mohamed I. Saad, Christian Aloe, et al. "Aspirin-Triggered Resolvin D1 Reduces Proliferation and the Neutrophil to Lymphocyte Ratio in a Mutant KRAS-Driven Lung Adenocarcinoma Model." Cancers 13, no. 13 (2021): 3224. http://dx.doi.org/10.3390/cancers13133224.
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Tumour-associated neutrophils (TANs) can support tumour growth by suppressing cytotoxic lymphocytes. AT-RvD1 is an eicosanoid that can antagonise neutrophil trafficking instigated by ALX/FPR2 ligands such as serum amyloid A (SAA). We aimed to establish whether SAA and ALOX5 expression associates with TANs and investigate the immunomodulatory actions of AT-RvD1 in vivo. MPO-positive neutrophils were quantified in tumour blocks from lung adenocarcinoma (n = 48) and control tissue (n = 20) by IHC. Tumour expression of SAA and ALOX5 were analysed by RTqPCR and an oncogenic KrasG12D lung adenocarcinoma mouse model was used to investigate the in vivo efficacy of AT-RvD1 treatment. ALOX5 expression was markedly reduced in lung adenocarcinoma tumours. The SAA/ALOX5 ratio strongly correlated with TANs and was significantly increased in tumours harbouring an oncogenic KRAS mutation. AT-RvD1 treatment reduced tumour growth in KrasG12D mice, which was accompanied by suppressed cellular proliferation within parenchymal lesions. In addition, AT-RvD1 significantly reduced the neutrophil to lymphocyte ratio (NLR), an established prognostic marker of poor survival in adenocarcinoma. This study identifies a novel molecular signature whereby elevated levels of SAA relative to ALOX5 favour accumulation of TANs. Furthermore, the ALOX5/5-LO enzymatic product, AT-RvD1, markedly reduced the NLR and suppressed tumour growth in KrasG12D mice.
9
Tan, Can Ozan, and Daniel Bullock. "A Dopamine–Acetylcholine Cascade: Simulating Learned and Lesion-Induced Behavior of Striatal Cholinergic Interneurons." Journal of Neurophysiology 100, no. 4 (2008): 2409–21. http://dx.doi.org/10.1152/jn.90486.2008.
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The giant cholinergic interneurons of the striatum are tonically active neurons (TANs) that respond with pauses to appetitive and aversive cues and to novel events. Whereas tonic activity emerges from intrinsic properties of these neurons, glutamatergic inputs from intralaminar thalamic nuclei and dopaminergic inputs from midbrain are required for genesis of pause responses. No prior computational models encompass both intrinsic and synaptically gated dynamics. We present a mathematical model that robustly accounts for behavior-related electrophysiological properties of TANs in terms of their intrinsic physiological properties and known afferents. In the model, balanced intrinsic hyperpolarizing and depolarizing currents engender tonic firing and glutamatergic inputs from thalamus (and cortex) both directly excite and indirectly inhibit TANs. If this inhibition, probably mediated by GABAergic nitric oxide synthase interneurons, exceeds a threshold, a persistent K+ conductance current amplifies its effect to generate a prolonged pause. Dopamine (DA) signals modulate both the intrinsic mechanisms and the external inputs of TANs. Simulations revealed that many learning-dependent behaviors of TANs, including acquired pauses to task-relevant cues, are explicable without recourse to learning-dependent changes in synapses onto TANs, due to a tight coupling between DA bursts and TAN pauses. These interactions imply that reward-predicting cues often cause striatal projection neurons to receive a cascade of signals: an adaptively scaled DA burst, a brief acetylcholine (ACh) burst, and an ACh pause. A sensitivity analysis revealed a unique TAN response surface, which shows that DA inputs robustly cooperate with thalamic inputs to control cue-dependent pauses of ACh release, which strongly affects performance- and learning-related dynamics in the striatum.
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Lad, Meeki, Angad Beniwal, Saket Jain, Sabraj Gill, and Manish Aghi. "TMIC-59. GLIOBLASTOMA INDUCES THE DIFFERENTIATION AND RECRUITMENT OF NON-CANONICAL ANTI-TUMORAL NEUTROPHILS FROM SKULL BONE MARROW." Neuro-Oncology 24, Supplement_7 (2022): vii284—vii285. http://dx.doi.org/10.1093/neuonc/noac209.1103.
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Abstract The effects of tumor-associated neutrophils (TANs) on glioblastoma biology remain poorly understood. Flow cytometric analysis of 5 newly diagnosed glioblastoma fresh tissue specimens surprisingly revealed a high fraction (21.0-34.1%) of TANs expressed MHCII, a marker of antigen-presenting cells not classically associated with neutrophils and not expressed in matched peripheral blood (PBNs). Transcriptomic profiling confirmed that patient TANs upregulated expression of MHCII subunits (HLA-DR), chaperones (HLA-DM), and costimulatory ligands (CD86/83). Ex vivo cocultures further demonstrated that TANs activated patient-matched naïve T cells in an MHCII-dependent manner, while PBNs did not (CD25 MFI fold-change: 1.1 vs 3.2, p&lt; 0.001). The antitumoral relevance of this property was confirmed in a syngeneic mouse glioma model, wherein αLy6G-mediated neutrophil depletion in T-cell-competent mice (Balb/c, n= 13) yielded endpoint tumors that had reduced CD8+ T cell infiltration (p= 0.0024) and were 2.4-fold larger by BLI (p= 0.0383) than controls, but had no bearing on tumor burden in T-cell-deficient (athymic) mice. Given the absence of MHCII+ neutrophils in circulation, we interrogated the inducibility of this phenotype by tumor-conditioned media in murine marrow/blood, finding that only immature Ly6Glow bone marrow neutrophils had sufficient plasticity to express MHCII and process foreign antigen as measured by DQ-ovalbumin uptake/proteolysis. Because of the non-inducibility of PBNs, we investigated the hypothesis that MHCII+ TANs were recruited to the glioblastoma microenvironment from adjacent skull bone marrow by labeling this space with CFMDA in tumor-implanted mice; at 72h, skull marrow-derived neutrophils contributed disproportionately to MHCII+ TANs compared to all TANs (41.7% vs 9.3%). As confirmation, in the first-ever scRNA-seq of human TANs, we demonstrated via pseudotime analysis that MHCII+ neutrophils represent a developmental lineage seen in TANs but not matched PBNs. Given the immunostimulatory effects of this population, mechanisms to promote neutrophil egress and tumor infiltration from the skull marrow may have therapeutic value.