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https://www.readbyqxmd.com/read/28806299/the-dynamic-and-transient-immune-microenvironment-in-locally-advanced-esophageal-adenocarcinoma-post-chemoradiation
#1
Ronan J Kelly, Ali H Zaidi, Matthew A Smith, Ashten N Omstead, Juliann E Kosovec, Daisuke Matsui, Samantha A Martin, Christina DiCarlo, E Day Werts, Jan F Silverman, David H Wang, Blair A Jobe
OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients...
August 10, 2017: Annals of Surgery
https://www.readbyqxmd.com/read/28791025/the-ido-ahr-axis-controls-th17-treg-immunity-in-a-pulmonary-model-of-fungal-infection
#2
Eliseu Frank de Araújo, Claudia Feriotti, Nayane Alves de Lima Galdino, Nycolas Willian Preite, Vera Lúcia Garcia Calich, Flávio Vieira Loures
In infectious diseases, the enzyme indoleamine 2,3 dioxygenase-1 (IDO1) that catalyzes the tryptophan (Trp) degradation along the kynurenines (Kyn) pathway has two main functions, the control of pathogen growth by reducing available Trp and immune regulation mediated by the Kyn-mediated expansion of regulatory T (Treg) cells via aryl hydrocarbon receptor (AhR). In pulmonary paracoccidioidomycosis (PCM) caused by the dimorphic fungus Paracoccidioides brasiliensis, IDO1 was shown to control the disease severity of both resistant and susceptible mice to the infection; however, only in resistant mice, IDO1 is induced by TGF-β signaling that confers a stable tolerogenic phenotype to dendritic cells (DCs)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28771034/in-silico-discovery-and-therapeutic-potential-of-ido1-and-tdo2-inhibitors
#3
Finith E Jernigan, Lijun Sun
No abstract text is available yet for this article.
August 3, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28771024/binding-properties-of-different-categories-of-ido1-inhibitors-a-microscale-thermophoresis-study
#4
Francesco Antonio Greco, Alice Coletti, Chiara Custodi, Daniela Dolciami, Alessandro Di Michele, Andrea Carotti, Maura Marinozzi, Nina Schlinck, Antonio Macchiarulo
AIM: Inhibition of IDO1 is a strategy pursued in the immune-oncology pipeline for the development of novel anticancer therapies. At odds with an ever-increasing number of inhibitors being disclosed in the literature and patent applications, only very few compounds have hitherto advanced in clinical settings. MATERIALS & METHODS: We have used MicroScale Thermophoresis analysis and docking calculations to assess on a quantitative basis the binding properties of distinct categories of inhibitors to IDO1...
August 3, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28768924/a-novel-high-throughput-virtual-screening-protocol-to-discover-new-indoleamine-2-3-dioxygenase-1-ido1-inhibitors
#5
Haojie Xu, Yunlong Song, Qing Yang
Indoleamine 2,3-dioxygenase 1 (IDO1) plays an important role in the immune escape of tumors and has emerged as a promising target for cancer immunotherapy. Despite its potential in immuno-oncology, very few chemotypes have been reported to date. Here, we disigned a novel high throughput virtual screening (HTVS) cascade protocol, combining both pharmacophore modeling and molecular docking and it was employed to query commercially available compounds to identify novel inhibitors. Among the 23 compounds selected for the in vitro IDO1 inhibitory activity assay, five compounds exhibit greater than 20% inhibition at a test concentration of 10 µM, with two compounds having an IC50 value of 23...
2017: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28765120/constitutive-ido1-expression-in-human-tumors-is-driven-by-cyclooxygenase-2-and-mediates-intrinsic-immune-resistance
#6
Marc Hennequart, Luc Pilotte, Stefania Cane, Delia Hoffmann, Vincent Stroobant, Etienne De Plaen, Benoît J Van den Eynde
Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. IDO1 is an immunosuppressive enzyme that degrades tryptophan. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE2), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways...
August 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28760910/epacadostat-shows-value-in-two-scchn-trials
#7
(no author information available yet)
In the ECHO-202/KEYNOTE-037 and ECHO-204 trials reported at the 2017 Annual Meeting of the American Society of Clinical Oncology, patients with squamous cell carcinoma of the head and neck responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. An IDO1 inhibitor, epacadostat also demonstrated promising activity in combination with the PD-1 checkpoint inhibitors in other solid tumors, including melanoma, urothelial carcinoma, renal cell carcinoma, and non-small cell lung cancer...
July 31, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28751450/infiltrating-t-cells-increase-ido1-expression-in-glioblastoma-and-contribute-to-decreased-patient-survival
#8
Lijie Zhai, Erik Ladomersky, Kristen L Lauing, Meijing Wu, Matthew Genet, Galina Gritsina, Balázs Győrffy, Priscilla K Brastianos, David Binder, Jeffrey A Sosman, Francis J Giles, C David James, Craig Horbinski, Roger Stupp, Derek A Wainwright
Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.<br /><br />Experimental Design: Patient-resected GBM, the cancer genome atlas, human T cell:GBM co-cultures, as well as nu/nu, NOD-scid and humanized (NSG-SGM3-BLT) mice engrafted human GBM, form the basis of our investigation...
July 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28733349/constitutive-ido1-expression-in-human-tumors-is-driven-by-cyclooxygenase-2-and-mediates-intrinsic-immune-resistance
#9
Marc Hennequart, Luc Pilotte, Stefania Cane, Delia Hoffmann, Vincent Stroobant, Etienne De Plaen, Benoît J Van den Eynde
Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. IDO1 is an immunosuppressive enzyme that degrades tryptophan. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE2), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways...
July 21, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28731684/the-binding-mode-of-n-hydroxyamidines-to-indoleamine-2-3-dioxygenase-1-ido1
#10
Ute F Röhrig, Vincent Zoete, Olivier Michielin
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through an N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or through the hydroxyamidine nitrogen atom. Here, we use quantum chemical calculations, docking, and quantum mechanics/molecular mechanics calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode...
July 27, 2017: Biochemistry
https://www.readbyqxmd.com/read/28726189/changing-the-properties-of-multipotent-mesenchymal-stromal-cells-by-ifn%C3%AE-administration
#11
N A Petinati, N M Kapranov, A E Bigil'deev, M D Popova, Yu O Davydova, I V Gal'tseva, N I Drize, L A Kuz'mina, E N Parovichnikova, V G Savchenko
We studied changes in the population of human multipotent mesenchymal stromal cells activated by IFNγ. The cells were cultured under standard conditions; IFNγ was added in various concentrations for 4 h or over 2 passages. It was shown that the total cell production significantly decreased after long-term culturing with IFNγ, but 4-h exposure did not affect this parameter. After 4-h culturing, the expression levels of IDO1, CSF1, and IL-6 increased by 300, 7, and 2.4 times, respectively, and this increase persisted 1 and 2 days after removal of IFNγ from the culture medium...
June 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28701757/oncolytic-measles-virus-enhances-antitumour-responses-of-adoptive-cd8-nkg2d-cells-in-hepatocellular-carcinoma-treatment
#12
Aiping Chen, Yonghui Zhang, Gang Meng, Dengxu Jiang, Hailin Zhang, Meihong Zheng, Mao Xia, Aiqin Jiang, Junhua Wu, Christian Beltinger, Jiwu Wei
There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8(+)NKG2D(+) cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8(+)NKG2D(+) cells, mediated by at least three distinct mechanisms...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698009/a-randomised-open-label-phase-2-study-of-the-ido1-inhibitor-epacadostat-incb024360-versus-tamoxifen-as-therapy-for-biochemically-recurrent-ca-125-relapse-only-epithelial-ovarian-cancer-primary-peritoneal-carcinoma-or-fallopian-tube-cancer
#13
Rebecca Kristeleit, Irina Davidenko, Vadim Shirinkin, Fatima El-Khouly, Igor Bondarenko, Michael J Goodheart, Vera Gorbunova, Carol A Penning, Jack G Shi, Xiangdong Liu, Robert C Newton, Yufan Zhao, Janet Maleski, Lance Leopold, Russell J Schilder
OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months)...
July 8, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28697066/viral-induced-modulation-of-multiple-checkpoint-proteins-in-cancers
#14
Gerard J Nuovo, Virginia A Folcik, Cynthia Magro
Therapy with checkpoint inhibitors represents a major advance in cancer treatment. The purpose of this study was to examine the expression patterns of the checkpoint proteins programmed death ligand 1 (PD L1), PD L2, indoleamine 2,3-dioxygenase 1 (IDO1), and cytotoxic T-lymphocyte antigen 4 (CTLA4) in cancers including those associated with viral infections. Normal, noninflamed tissues rarely express checkpoint proteins with exceptions including the placenta and stomach. Expression of PD L1 was noted in 30%, PD L2 in 18%, IDO1 in 13%, and CTLA4 in 14% of 333 nonviral malignancies including endometrial, ovarian, lung, and breast cancers...
July 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/28689792/functional-role-of-kynurenine-and-aryl-hydrocarbon-receptor-axis-in-chronic-rhinosinusitis-with-nasal-polyps
#15
Heng Wang, Danh C Do, Jinxin Liu, Baofeng Wang, Jingjing Qu, Xia Ke, Xiaoyan Luo, Ho Man Tang, Ho Lam Tang, Chengping Hu, Mark E Anderson, Zheng Liu, Peisong Gao
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell-mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). OBJECTIVES: Determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. METHODS: We measured expression of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls...
July 6, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28687008/association-of-breast-carcinoma-growth-with-a-non-canonical-axis-of-ifn%C3%AE-ido1-tsp1
#16
Bruno Lopes-Bastos, Liang Jin, Fiona Ruge, Sioned Owen, Andrew Sanders, Christopher Cogle, John Chester, Wen G Jiang, Jun Cai
Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the first and rate-limited step of tryptophan breakdown...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28667875/discovery-of-potent-ido1-inhibitors-derived-from-tryptophan-using-scaffold-hopping-and-structure-based-design-approaches
#17
Yi Zou, Yan Wang, Fang Wang, Minghao Luo, Yuezhen Li, Wen Liu, Zhangjian Huang, Yihua Zhang, Wenjie Guo, Qiang Xu, Yisheng Lai
Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e, 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells...
June 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28662235/use-of-pd-1-targeting-macrophage-infiltration-and-ido-pathway-activation-in-sarcomas-a-phase-2-clinical-trial
#18
Maud Toulmonde, Nicolas Penel, Julien Adam, Christine Chevreau, Jean-Yves Blay, Axel Le Cesne, Emmanuelle Bompas, Sophie Piperno-Neumann, Sophie Cousin, Thomas Grellety, Thomas Ryckewaert, Alban Bessede, François Ghiringhelli, Marina Pulido, Antoine Italiano
Importance: There is a strong rationale for treating sarcomas with immunotherapy. Objective: To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. Design, Setting, and Participants: This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST)...
June 29, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28659861/the-effect-of-systemic-nitroglycerin-administration-on-the-kynurenine-pathway-in-the-rat
#19
Gábor Nagy-Grócz, Klaudia F Laborc, Gábor Veres, Attila Bajtai, Zsuzsanna Bohár, Dénes Zádori, Annamária Fejes-Szabó, Eleonóra Spekker, László Vécsei, Árpád Párdutz
The primary headache disorders include migraine, which is one of the most frequent neurological disorders, which influences more than 14% of the whole population. Despite the research efforts, its exact pathomechanism is not fully revealed, but evidence points to the role of glutamate and its receptors. Kynurenic acid is an endogenous glutamate receptor antagonist produced by the kynurenine pathway (KP). Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) convert l-tryptophan to N-formyl-l-kynurenine, to be further transformed to l-kynurenine...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28650043/heme-containing-enzymes-and-inhibitors-for-tryptophan-metabolism
#20
REVIEW
Daojing Yan, Ying-Wu Lin, Xiangshi Tan
Iron-containing enzymes such as heme enzymes play crucial roles in biological systems. Three distinct heme-containing dioxygenase enzymes, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the initial and rate-limiting step of l-tryptophan catabolism through the kynurenine pathway in mammals. Overexpression of these enzymes causes depletion of tryptophan and the accumulation of metabolic products, which contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies...
June 26, 2017: Metallomics: Integrated Biometal Science
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