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https://www.readbyqxmd.com/read/29787958/altered-tryptophan-catabolite-concentrations-in-major-depressive-disorder-and-associated-changes-in-hippocampal-subfield-volumes
#1
Kelly Doolin, Kelly A Allers, Sina Pleiner, Andre Liesener, Chloe Farrell, Leonardo Tozzi, Erik O'Hanlon, Darren Roddy, Thomas Frodl, Andrew Harkin, Veronica O'Keane
BACKGROUND: Tryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC)...
May 19, 2018: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/29777939/variation-of-genes-encoding-kat1-aadat-and-ido1-as-a-potential-risk-of-depression-development
#2
Paulina Wigner, Piotr Czarny, Ewelina Synowiec, Michał Bijak, Monika Talarowska, Piotr Galecki, Janusz Szemraj, Tomasz Sliwinski
Numerous data suggests that the disorders of tryptophan catabolites (TRYCATs) pathway, including a decreased level of tryptophan or evaluated concentration of harmful TRYCATs -kynurenine, quinolinic acid, 3-hydroxyanthranilic acid, 3-hydroxytryptophan - may cause the occurrence of DD symptoms. In this work, we assessed the relationship between single-nucleotide polymorphisms (SNPs) of KAT1, KAT2 and IDO1 gene encoding, and the risk of depression development. Our study was performed on the DNA isolated from peripheral blood of 281 depressed patients and 236 controls...
May 16, 2018: European Psychiatry: the Journal of the Association of European Psychiatrists
https://www.readbyqxmd.com/read/29770915/cytolytic-activity-score-to-assess-anticancer-immunity-in-colorectal-cancer
#3
Sumana Narayanan, Tsutomu Kawaguchi, Li Yan, Xuan Peng, Qianya Qi, Kazuaki Takabe
BACKGROUND: Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity. METHODS: Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA)...
May 16, 2018: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/29760410/motivational-changes-that-develop-in-a-mouse-model-of-inflammation-induced-depression-are-independent-of-indoleamine-2-3-dioxygenase
#4
Elisabeth G Vichaya, Geoffroy Laumet, Diana L Christian, Aaron J Grossberg, Darlene J Estrada, Cobi J Heijnen, Annemieke Kavelaars, Robert Dantzer
Despite years of research, our understanding of the mechanisms by which inflammation induces depression is still limited. As clinical data points to a strong association between depression and motivational alterations, we sought to (1) characterize the motivational changes that are associated with inflammation in mice, and (2) determine if they depend on inflammation-induced activation of indoleamine 2,3 dioxygenase-1 (IDO1). Lipopolysaccharide (LPS)-treated or spared nerve injured (SNI) wild type (WT) and Ido1 -/- mice underwent behavioral tests of antidepressant activity (e...
April 27, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29754847/feasibility-of-classification-of-triple-negative-breast-cancer-by-immunohistochemical-surrogate-markers
#5
Sewha Kim, Byung-In Moon, Woosung Lim, Sanghui Park, Min Sun Cho, Sun Hee Sung
INTRODUCTION: Recently, Burstein et al identified 4 stable molecular subtypes of triple negative breast cancer (TNBC) by mRNA profiling: luminal androgen receptor (LAR), mesenchymal (MES), basal-like immune-activated (BLIA), and basal-like immune-suppressive (BLIS) types. The purpose of this study was to assess the feasibility of immunohistochemistry (IHC) surrogate panel in classifying the TNBC molecular subtypes using a large cohort of TNBC retrieved from a single institution. MATERIALS AND METHODS: IHC for androgen receptor [AR], claudin-3, E-cadherin, cytokeratin 5/6 [CK5/6], epidermal growth factor receptor [EGFR], indoleamine 2,3-dioxygenase 1 [IDO1], and Forkhead box C1 [FOXC1] were performed using the tissue microarray constructed from 200 TNBC samples...
March 23, 2018: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29746927/indoleamine-2-3-dioxygenase-1-inhibition-targets-anti-pd1-resistant-lung-tumors-by-blocking-myeloid-derived-suppressor-cells
#6
Ailin Li, Hampartsoum B Barsoumian, Jonathan E Schoenhals, Taylor R Cushman, Mauricio S Caetano, Xiaohong Wang, David R Valdecanas, Sharareh Niknam, Ahmed I Younes, Guang Li, Wendy A Woodward, Maria Angelica Cortez, James W Welsh
Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R...
May 7, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29746559/comparative-genotypic-and-phenotypic-analysis-of-human-peripheral-blood-monocytes-and-surrogate-monocyte-like-cell-lines-commonly-used-in-metabolic-disease-research
#7
Darren M Riddy, Emily Goy, Philippe Delerive, Roger J Summers, Patrick M Sexton, Christopher J Langmead
Monocyte-like cell lines (MCLCs), including THP-1, HL-60 and U-937 cells, are used routinely as surrogates for isolated human peripheral blood mononuclear cells (PBMCs). To systematically evaluate these immortalised cells and PBMCs as model systems to study inflammation relevant to the pathogenesis of type II diabetes and immuno-metabolism, we compared mRNA expression of inflammation-relevant genes, cell surface expression of cluster of differentiation (CD) markers, and chemotactic responses to inflammatory stimuli...
2018: PloS One
https://www.readbyqxmd.com/read/29745343/indazoles-derivatives-promising-anti-tumor-agents
#8
Yichao Wan, Shengzhuo He, Wei Li, Zilong Tang
Currently, cancer continues being a dramatically increasing and serious threat to public health. Although many anti-tumor agents have been developed in recent years, the survival rate of patients is not satisfactory. The poor prognosis of cancer patients is closely related to the occurrence of drug resistance. Therefore, it is urgent to develop new anti-tumor agents to make up for the deficiency. Indazoles is an important class of heterocyclic compounds possessing a variety of biological activities, such as anti-tumor, anti-bacterial, anti-inflammatory, anti-depressant and anti-hypertensive...
May 9, 2018: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29740718/combination-immunotherapy-in-non-small-cell-lung-cancer
#9
REVIEW
Melina E Marmarelis, Charu Aggarwal
PURPOSE OF REVIEW: Checkpoint blockade has changed the treatment landscape in non-small cell lung cancer (NSCLC), but single-agent approaches are effective for only a select subset of patients. Here, we will review the evidence for combination immunotherapies in NSCLC and the clinical data evaluating the efficacy of this approach. RECENT FINDINGS: Clinical trials evaluating combination PD-1 and CTLA-4 blockade as well as PD-1 in combination with agents targeting IDO1, B7-H3, VEGF, and EGFR show promising results...
May 8, 2018: Current Oncology Reports
https://www.readbyqxmd.com/read/29722898/lw106-a-novel-inhibitor-of-ido1-suppresses-tumor-progression-by-limiting-stroma-immune-crosstalk-and-cancer-stem-cell-enrichment-in-the-tumor-microenvironment
#10
Rong Fu, Yi-Wei Zhang, Hong-Mei Li, Wen-Cong Lv, Li Zhao, Qing-Long Guo, Tao Lu, Stephen J Weiss, Zhi-Yu Li, Zhao-Qiu Wu
BACKGROUND AND PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumors characterized by dysregulated tryptophan metabolism. However, the antitumor efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumor effects and the underlying mechanisms in two Tumor models...
May 3, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29691296/tryptophan-metabolism-contributes-to-radiation-induced-immune-checkpoint-reactivation-in-glioblastoma
#11
Pravin Kesarwani, Antony Prabhu, Shiva Kant, Praveen Kumar, Stewart F Graham, Katie L Buelow, George D Wilson, Christopher Ryan Miller, Prakash Chinnaiyan
PURPOSE: Immune checkpoint inhibitors designed to revert tumor-induced immune suppression have emerged as potent anti-cancer therapies. Tryptophan metabolism represents an immune checkpoint and targeting this pathway's rate limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).  Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma...
April 24, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29685162/mir-153-suppresses-ido1-expression-and-enhances-car-t-cell-immunotherapy
#12
Qian Huang, Jiajia Xia, Lei Wang, Xu Wang, Xiaodong Ma, Qipan Deng, Yong Lu, Munish Kumar, Zhiyuan Zhou, Ling Li, Zhaoyang Zeng, Ken H Young, Qing Yi, Mingzhi Zhang, Yong Li
BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting step in converting tryptophan to kynurenine. Chimeric antigen receptor (CAR) T cells are T cells with recombinant receptors targeting tumor-associated antigens. The Food and Drug Administration has approved CAR T cells that target CD19 for treatment of advanced B cell leukemia and lymphoma. However, CAR T cell therapy in solid tumors has been hampered by multiple obstacles. Preclinical and clinical studies suggest that combinatorial immune checkpoint blockade and IDO1 inhibition provide durable therapeutic efficacy against cancer...
April 23, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29670692/discovery-of-novel-indoleamine-2-3-dioxygenase-1-ido1-and-histone-deacetylase-hdac-dual-inhibitors
#13
Kun Fang, Guoqiang Dong, Yu Li, Shipeng He, Ying Wu, Shanchao Wu, Wei Wang, Chunquan Sheng
In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma...
April 12, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29667084/investigation-of-the-aryl-hydrocarbon-receptor-and-the-intrinsic-tumoral-component-of-the-kynurenine-pathway-of-tryptophan-metabolism-in-primary-brain-tumors
#14
Anthony R Guastella, Sharon K Michelhaugh, Neil V Klinger, Hassan A Fadel, Sam Kiousis, Rouba Ali-Fehmi, William J Kupsky, Csaba Juhász, Sandeep Mittal
INTRODUCTION: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment. METHODS: We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites...
April 17, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29666190/tryptophanyl-trna-synthetase-mediates-high-affinity-tryptophan-uptake-into-human-cells
#15
Miki Miyanokoshi, Takumi Yokosawa, Keisuke Wakasugi
The tryptophan (Trp) transport system has a high affinity and selectivity toward Trp, and has been reported to exist in both human and mouse macrophages. Although this system is highly expressed in interferon-γ (IFN-γ)-treated cells and indoleamine 2,3-dioxygenase 1 (IDO1)-expressing cells, its identity remains incompletely understood. Tryptophanyl-tRNA synthetase (TrpRS) is also highly expressed in IFN-γ-treated cells and also has high affinity and selectivity for Trp. Here, we investigated the effects of human TrpRS expression on Trp uptake into IFN-γ-treated human THP-1 monocytes or HeLa cells...
April 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29651242/discovery-of-novel-inhibitors-of-indoleamine-2-3-dioxygenase-1-through-structure-based-virtual-screening
#16
Guoqing Zhang, Jing Xing, Yulan Wang, Lihao Wang, Yan Ye, Dong Lu, Jihui Zhao, Xiaomin Luo, Mingyue Zheng, Shiying Yan
Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric heme-containing enzyme that catalyzes the first and the rate limiting step in catabolism of tryptophan via the kynurenine (KYN) pathway, which plays a significant role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for anticancer therapy and chronic viral infections. In the present study, a class of IDO1 inhibitors with novel scaffolds were identified by virtual screening and biochemical validation, in which the compound DC-I028 shows moderate IDO1 inhibitory activity with an IC50 of 21...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29618666/peptide-vaccine-immunotherapy-biomarkers-and-response-patterns-in-pediatric-gliomas
#17
Sören Müller, Sameer Agnihotri, Karsen E Shoger, Max I Myers, Nicholas Smith, Srilakshmi Chaparala, Clarence R Villanueva, Ansuman Chattopadhyay, Adrian V Lee, Lisa H Butterfield, Aaron Diaz, Hideho Okada, Ian F Pollack, Gary Kohanbash
Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points...
April 5, 2018: JCI Insight
https://www.readbyqxmd.com/read/29615752/endothelial-indoleamine-2-3-dioxygenase-1-regulates-the-placental-vascular-tone-and-is-deficient-in-intrauterine-growth-restriction-and-pre-eclampsia
#18
Pablo Zardoya-Laguardia, Astrid Blaschitz, Birgit Hirschmugl, Ingrid Lang, Sereina A Herzog, Liudmila Nikitina, Martin Gauster, Martin Häusler, Mila Cervar-Zivkovic, Eva Karpf, Ghassan J Maghzal, Chris P Stanley, Roland Stocker, Christian Wadsack, Saša Frank, Peter Sedlmayr
Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE)...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29607498/1-l-mt-an-ido-inhibitor-prevented-colitis-associated-cancer-by-inducing-cdc20-inhibition-mediated-mitotic-death-of-colon-cancer-cells
#19
Xiuting Liu, Wei Zhou, Xin Zhang, Yang Ding, Qianming Du, Rong Hu
Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells...
April 1, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29595533/ido1-expression-is-associated-with-immune-tolerance-and-poor-prognosis-in-patients-with-surgically-resected-esophageal-cancer
#20
Yuki Kiyozumi, Yoshifumi Baba, Kazuo Okadome, Taisuke Yagi, Takatsugu Ishimoto, Masaaki Iwatsuki, Yuji Miyamoto, Naoya Yoshida, Masayuki Watanabe, Yoshihiro Komohara, Hideo Baba
OBJECTIVES: To evaluate the relationship between indoleamine 2, 3-dioxygenase (IDO1) expression and tumoral immune status and clinical outcome in esophageal cancer. SUMMARY BACKGROUND DATA: IDO1 is a primary enzyme that generates immunosuppressive metabolites such as tryptophan and kynurenine. Like the PD-1/PD-L1 pathway, IDO1 plays a major role in tumor immunology and is a potential immune-based therapeutic target. METHODS: The expressions of IDO1, CD8 (a marker of cytotoxic T cells), FOXP3 [a marker of regulatory T cells (Treg)], and PD-L1 in 305 curatively resected esophageal cancers were evaluated by immunostaining...
March 27, 2018: Annals of Surgery
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