scholarly journals Clinical Relevance for Circulating Cold Inducible RNA-Binding Protein (CIRP) in Patients with ASD

2020 ◽  
Author(s):  
Yuya Fujita ◽  
Toru Yago ◽  
Tomoyuki Asano ◽  
Haruki Matsumoto ◽  
Naoki Matsuoka ◽  
...  
Keyword(s):  
Disease Activity ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Serum Samples ◽  
Potential Biomarker ◽  
Significant Difference

Abstract Background: Adult Still’s disease (ASD) is a systemic autoinflammatory disease, in which danger-associated molecular patterns (DAMPs)-mediated inflammasome activation seems to be involved in the disease pathogenesis. Cold inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cellular stress and has been identified as a DAMP that triggers the inflammatory response. The aim of this study is to investigate the clinical significance of serum CIRP levels in ASD.Methods: Serum samples were obtained from 42 patients with active ASD or 50 patients with rheumatoid arthritis (RA) and 15 healthy control patients (HCs). Serum levels of CIRP and IL-18 were determined using enzyme-linked immunosorbent assay and compared with 42 patients with ASD or 50 patients with RA and 15 HCs. Results were also analyzed according to the clinical features of ASD.Results: Serum CIRP levels were significantly higher in patients with ASD compared with patients with RA (median: 9.6 ng/mL, IQR [5.7–14.4] versus 3.2 ng/mL, IQR [1.9–3.8]; p < 0.001) and with HCs (2.8 ng/mL, [IQR; 1.4–4.9], p < 0.001). There was a significant positive correlation between serum CIRP levels and ASD disease activity score (Pouchet’s score r=0.45, p=0.003) as well as between ASD-specific biomarkers ferritin and IL-18. However, there was no significant difference in the serum CIRP levels among ASD patients with three different disease phenotypes. Intracellular CIRP expression on CD14+ monocytes was elevated in patients with ASD compared with those in patients in RA.Conclusion: These results suggest that CIRP may play a significant role in the pathophysiology of ASD and could be a potential biomarker for monitoring the disease activity of ASD.

scholarly journals Clinical relevance for circulating cold-inducible RNA-binding protein (CIRP) in patients with adult-onset Still’s disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255493
Author(s):  
Yuya Fujita ◽  
Toru Yago ◽  
Tomoyuki Asano ◽  
Haruki Matsumoto ◽  
Naoki Matsuoka ◽  
...  
Keyword(s):  
Disease Activity ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Adult Onset Still’S Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Adult Onset Still's Disease

Background Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease in which danger-associated molecular patterns (DAMPs)-mediated inflammasome activation seems to be involved in the disease pathogenesis. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cellular stress and has been identified as a DAMP that triggers the inflammatory response. The aim of this study is to investigate the clinical significance of serum CIRP levels in AOSD. Methods Serum samples were obtained from 44 patients with active AOSD or 50 patients with rheumatoid arthritis (RA), 20 patients with systemic lupus erythematosus (SLE), and 15 healthy control patients (HCs). Serum levels of CIRP and IL-18 were determined using enzyme-linked immunosorbent assay. Results were compared among AOSD patients, RA patients, SLE patients and HCs. Results were also analyzed according to the clinical features of AOSD. Results Serum CIRP levels were significantly higher in AOSD patients compared with RA patients (median: 9.6 ng/mL, IQR [5.7–14.4] versus 3.2 ng/mL, IQR [1.9–3.8]; p < 0.001) and with HCs (2.8 ng/mL, [IQR; 1.4–4.9], p < 0.001). There was a significant positive correlation between serum CIRP levels and AOSD disease activity score (Pouchot’s score r = 0.45, p = 0.003) as well as between AOSD-specific biomarkers ferritin and IL-18. However, there was no significant difference in the serum CIRP levels among AOSD patients with three different disease phenotypes. Conclusions These results suggest that CIRP may play a significant role in the pathophysiology of AOSD and could be a potential biomarker for monitoring the disease activity of AOSD.

scholarly journals Cold-Inducible RNA-Binding Protein (CIRP) Potentiates Uric Acid-Induced IL-1β Production

2021 ◽  
Author(s):  
Yuya Fujita ◽  
Toru Yago ◽  
Haruki Matsumoto ◽  
Tomoyuki Asano ◽  
Naoki Matsuoka ◽  
...  
Keyword(s):  
Uric Acid ◽  
Nlrp3 Inflammasome ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Human Neutrophils ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Caspase 1

Abstract Background Gout is an autoinflammatory disease driven by interleukin-1 (IL-1) induction in response to uric acid crystals. IL-1β production is dependent on inflammasome activation, which requires a priming signal, followed by an activating signal. The cold-inducible RNA-binding protein (CIRP) has been recently identified as a damage-associated molecular pattern (DAMP). In this study, we evaluated the roles of CIRP in monosodium urate (MSU)-mediated IL-1β secretion using human neutrophils. Methods Human neutrophils were stimulated by MSU in the presence or absence of CIRP priming to determine NLRP3 inflammasome activation and subsequent caspase-1 activation and IL-1β production. Cellular supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) to determine the presence of IL-1β or caspase-1 (p20). The cellular supernatants and lysates were also analyzed by immunoblotting using anti-cleaved IL-1β or anti-cleaved caspase-1 antibodies. Additionally, pro-IL-1β and NLRP3 transcript levels were analyzed by real-time reverse transcription-PCR (RT-PCR). Results Neither CIRP nor MSU stimulation alone induced sufficient IL-1β secretion from neutrophils. However, MSU stimulation induced IL-1β secretion from CIRP-primed neutrophils in a dose-dependent manner. This MSU-induced IL-1β secretion from CIRP-primed neutrophils was accompanied by the induction of cleaved IL-1β (p17). Furthermore, cleaved caspase-1 was induced in the cellular lysates of CIRP/MSU-treated neutrophils. Additionally, CIRP stimulation induced the expression of pro-IL-1β mRNA and protein in neutrophils. Conclusions Our data indicate that CIRP, an endogenous stress molecule, triggers uric acid-induced mature IL-1β induction as a priming stimulus for NLRP3 inflammasome in human neutrophils. We propose that CIRP acts as an important proinflammatory stimulant that primes and activates inflammasome and pro-IL-1β processing in response to uric acid in innate immune cells.

scholarly journals Cold-inducible RNA-binding protein (CIRP) potentiates uric acid-induced IL-1β production

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Yuya Fujita ◽  
Toru Yago ◽  
Haruki Matsumoto ◽  
Tomoyuki Asano ◽  
Naoki Matsuoka ◽  
...  
Keyword(s):  
Uric Acid ◽  
Nlrp3 Inflammasome ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Human Neutrophils ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Caspase 1

Abstract Background Gout is an autoinflammatory disease driven by interleukin-1 (IL-1) induction in response to uric acid crystals. IL-1β production is dependent on inflammasome activation, which requires a priming signal, followed by an activating signal. The cold-inducible RNA-binding protein (CIRP) has been recently identified as a damage-associated molecular pattern (DAMP). In this study, we evaluated the roles of CIRP in monosodium urate (MSU)-mediated IL-1β secretion using human neutrophils. Methods Human neutrophils were stimulated by MSU in the presence or absence of CIRP priming to determine NLRP3 inflammasome activation and subsequent caspase-1 activation and IL-1β production. Cellular supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) to determine the presence of IL-1β or caspase-1 (p20). The cellular supernatants and lysates were also analyzed by immunoblotting using anti-cleaved IL-1β or anti-cleaved caspase-1 antibodies. Results Neither CIRP nor MSU stimulation alone induced sufficient IL-1β secretion from neutrophils. However, MSU stimulation induced IL-1β secretion from CIRP-primed neutrophils in a dose-dependent manner. This MSU-induced IL-1β secretion from CIRP-primed neutrophils was accompanied by the induction of cleaved IL-1β (p17), which was inhibited by the pretreatment of MCC950, a specific inhibitor for NLRP3. Furthermore, cleaved caspase-1 was induced in the cellular lysates of CIRP/MSU-treated neutrophils. Additionally, CIRP stimulation induced the protein expression of pro-IL-1β in neutrophils. Conclusions Our data indicate that CIRP, an endogenous stress molecule, triggers uric acid-induced mature IL-1β induction as a priming stimulus for NLRP3 inflammasome in human neutrophils. We propose that CIRP acts as an important proinflammatory stimulant that primes and activates inflammasome and pro-IL-1β processing in response to uric acid in innate immune cells.

scholarly journals Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

2020 ◽  
Author(s):  
Yuya Fujita ◽  
Tomoyuki Asano ◽  
Haruki Matsumoto ◽  
Naoki Matsuoka ◽  
Jumpei Temmoku ◽  
...  
Keyword(s):  
Disease Activity ◽  
Immunosuppressive Treatment ◽  
Elevated Serum ◽  
Serum Levels ◽  
Chronic Arthritis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Still’S Disease ◽  
Serum Samples ◽  
Still's Disease ◽  
Adult Still's Disease

Abstract Background: The interaction between galectin-9 (Gal-9) and its ligand, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), one of the coinhibitory receptors, transduce the inhibitory signaling to regulate immune responses. The dysregulated expression of checkpoint molecules has been reported under various inflammatory or autoimmune conditions. The aim of this study is to investigate the levels of these checkpoint molecules and their associations between proinflammatory markers in patients with adult Still’s disease (ASD). Methods: Serum samples were collected from 47 patients with active ASD, 116 patients with rheumatoid arthritis (RA), and 37 healthy controls (HCs). Serum levels of Gal-9, soluble TIM-3 (sTIM-3), and IL-18 were determined using enzyme-linked immunosorbent assay (ELISA). Results were compared with clinical features of ASD. Results: Serum Gal-9 levels in patients with ASD (median: 21.57 ng/ml, interquartile range IQR [11.41–39.72]) were significantly higher compared to those in patients with RA (7.58 ng/ml, IQR [5.57–10.20] p < 0.001) as well as those in HCs (4.51 ng/ml, [IQR; 3.58–5.45], p < 0.001). Similarly, serum sTIM-3 levels in patients with ASD were significantly higher than those in patients with RA and HCs. Serum levels of Gal-9 or sTIM-3 showed positive correlations with IL-18 levels (Gal-9; r = 0.90, p< 0.001, sTIM-3; r = 0.78, p< 0.001) in patients with ASD. Serum levels of Gal-9 or sTIM-3 correlated with serum ferritin (Gal-9; r = 0.77, p< 0.001, sTIM-3; r = 0.71, p< 0.001) and ASD disease activity score (Pouchot’s score, Gal-9; r = 0.66, p< 0.001, sTIM-3; r = 0.59, p< 0.001). Whereas there was no significant correlation between serum Gal-9 or sTIM-3 and CRP. ASD patients with chronic arthritis phenotype had a significantly higher Gal-9/ferritin and sTIM-3/ferritin ratio than those without this phenotype. After immunosuppressive treatment, Gal-9 and sTIM-3 levels showed a significant decline in parallel to the disease activity scores. Conclusions: Serum levels of the coinhibitory checkpoint molecules were elevated and correlated with disease activity in patients with ASD. These coinhibitory checkpoint molecule may be implicated in the autoinflammatory process seen in ASD.

scholarly journals Identification and Validation of RNA Binding Protein-associated Prognostic Model for Neuroblastoma

2020 ◽  
Author(s):  
JUN YANG ◽  
Jiaying Zhou ◽  
Cuili Li ◽  
Shaohua Wang
Keyword(s):  
Survival Rate ◽  
Prognostic Model ◽  
Rna Binding ◽  
Binding Protein ◽  
Characteristic Curve ◽  
Rna Binding Protein ◽  
Receiver Operator Characteristic Curve ◽  
Validation Data ◽  
Data Set ◽  
Significant Difference

Abstract Background: The abnormal expression of RNA binding protein (RBP) may be related to the development and progress of cancer. However, little is known about the mechanism of RBP in neuroblastoma (NB). Methods: We downloaded the RNA expression data of NB and normal nervous tissues from the (TARGET) database and GTEx database, and determined the differential expression of RBP between normal and cancerous tissues. Then the function and prognostic value of these RBPs were systematically studied. Results: A total of 348 differentially expressed RBPs were identified, together with 166 up-regulated RBPs and 182 down-regulated RBPs. Two hub RBPs (CPEB3 and CTU1) were identified as prognostic-related genes and chose to build prognostic risk score models. Further analysis showed that based on this model, the overall survival rate of patients in the high-risk subgroup was lower (P=2.152e-04). The area under the curve(AUC) of the receiver-operator characteristic curve(ROC) of the prognostic model is 0.720 in the TARGET cohort. There is a significant difference in the survival rate of patients in the high and low risk subgroups in the validation data set GSE85047 (P = 0.1237e-08), the AUC is 0.730. Conclusions: RNA binding protein (CPEB3 and CTU1) can be used as molecular markers of NB.

scholarly journals Identification and validation of RNA binding protein-associated prognostic model for Neuroblastoma

2021 ◽  
Author(s):  
Jun Yang ◽  
Jiaying Zhou ◽  
Cuili Li ◽  
Shaohua Wang
Keyword(s):  
Survival Rate ◽  
Prognostic Model ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Characteristic Curve ◽  
Rna Binding Protein ◽  
Validation Data ◽  
Data Set ◽  
Significant Difference

Abstract ABSTRACT Background: The abnormal expression of RNA binding protein (RBP) may be related to the development and progress of cancer. However, little is known about the mechanism of RBP in neuroblastoma (NB). Methods: We downloaded the RNA expression data of NB and normal nervous tissues from the (TARGET) database and GTEx database, and determined the differential expression of RBP between normal and cancerous tissues. Then the function and prognostic value of these RBPs were systematically studied. Results: A total of 348 differentially expressed RBPs were identified, together with 166 up-regulated RBPs and 182 down-regulated RBPs. Two hub RBPs (CPEB3 and CTU1) were identified as prognostic-related genes and chose to build prognostic risk score models. Further analysis showed that based on this model, the overall survival rate of patients in the high-risk subgroup was lower (P=2.152e-04). The area under the curve(AUC) of the receiver-operator characteristic curve(ROC) of the prognostic model is 0.720 in the TARGET cohort. There is a significant difference in the survival rate of patients in the high and low risk subgroups in the validation data set GSE85047 (P = 0.1237e-08), the AUC is 0.730. Conclusions: RNA binding protein (CPEB3 and CTU1) can be used as molecular markers of NB. Keywords: Neuroblastoma, RNA binding proteins, prognostic, TARGET, GTEx

scholarly journals Circ_0000079 Decoys the RNA-Binding Protein FXR1 to Interrupt Formation of the FXR1/PRCKI Complex and Decline Their Mediated Cell Invasion and Drug Resistance in NSCLC

2020 ◽  
Vol 29 ◽  
pp. 096368972096107
Author(s):  
Chen Chen ◽  
Min Zhang ◽  
Yan Zhang
Keyword(s):  
Drug Resistance ◽  
Cell Invasion ◽  
Rna Binding ◽  
Binding Protein ◽  
Glycogen Synthesis ◽  
Rna Binding Protein ◽  
Cell Counting ◽  
Mesenchymal Transition ◽  
Potential Biomarker ◽  
Nsclc Patients

Nonsmall cell lung cancer (NSCLC) has gradually become one of the deadliest threats to human health and life worldwide. Although reports have shown that circular RNAs (circRNAs) are associated with progression and metastasis of NSCLC, the biological functions of circRNAs during these processes remain largely unknown. Our study showed that circ_0000079 (CiR79) levels were significantly downregulated in NSCLC patients, especially in cisplatin (DDP)-resistant NSCLC patients, and low circ_0000079 levels were significantly associated with poor overall survival of NSCLC patients. Then, results from Cell Counting Kit-8 (CCK-8) cell viability assay and transwell cell invasion assay in A549/DDP and H460/DDP cells transfected with pCDH-CiR79 expression vector showed that circ_0000079 overexpression significantly inhibited cell proliferation and invasion of these DDP-resistant NSCLC cells. The online bioinformatic program StarBase and RNA-binding protein immunoprecipitation predicted and demonstrated that circ_0000079 could bind with the Fragile X-Related 1 (FXR1) protein rather than with protein kinase C, iota (PRKCI), which was shown to form a complex with FXR1 to promote invasion and growth of NSCLC cells. Co-immunoprecipitation combined with Western blot assays indicated that FXR1 levels were remarkably decreased, but PRKCI levels remained unchanged in pCDH-ciR79 transfected NSCLC cells. Moreover, circ_0000079 negatively regulated FXR1/PRKCI-mediated phosphorylation of glycogen synthesis kinase 3β and activator protein 1, thus suppressing the protein level of the Snail gene, an important promoter gene regulating cancer cell growth and epithelial-mesenchymal transition. Furthermore, DDP resistance of A549/DDP and H460/DDP cells was inhibited by circ_0000079 overexpression but was restored by FXR1. Hence, our findings demonstrated that circ_0000079 might inhibit cell invasion and drug resistance in NSCLC by interrupting the formation of the FXR1/PRCKI complex by interacting with FXR1, and circ_0000079 could act as a potential biomarker and therapeutic target for NSCLC.

scholarly journals Serum adipokine profiles in patients with microscopic polyangiitis and granulomatosis with polyangiitis: An exploratory analysis

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254226
Author(s):  
Sung Soo Ahn ◽  
Taejun Yoon ◽  
Jason Jungsik Song ◽  
Yong-Beom Park ◽  
Sang-Won Lee
Keyword(s):  
Disease Activity ◽  
Granulomatosis With Polyangiitis ◽  
Clinical Laboratory ◽  
Microscopic Polyangiitis ◽  
Laboratory Data ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Laboratory Findings ◽  
Reactive Protein ◽  
Potential Biomarker

Objectives Previous studies have shown that adipokines may serve as potential biomarkers reflecting disease activity in various autoimmune diseases. Here, we investigated the relationship between four adipokines and clinical/laboratory findings in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Methods Sera from 63 patients with MPA and GPA who were registered in a prospective cohort were used to detect serum levels of adiponectin, chemerin, resistin, and vaspin using commercial enzyme-linked immunosorbent assay kits. Associations between adipokines and clinical and laboratory data was assessed using Pearson’s correlation analysis. Results The median age was 65.0 years, 24 patients were male, and 42 patients were diagnosed with MPA. The median levels of adiponectin, chemerin, resistin, and vaspin in patient sera were 13.9 ng/mL, 9.2 ng/mL, 23.7 ng/mL, and 0.1 ng/mL, respectively. A significant correlation between chemerin level and five-factor score (FFS) was found (r = 0.320, p = 0.011), and resistin was correlated with both Birmingham vasculitis activity score and FFS (r = 0.256, p = 0.043 and r = 0.320, p = 0.011). Regarding laboratory data, adiponectin level was associated with creatinine, and chemerin level was associated with creatinine, albumin, and erythrocyte sedimentation rate (ESR). On the other hand, resistin was found to be associated with white blood cell count, creatinine, ESR, and C-reactive protein. Age did not have a significant impact on the levels of adipokines. Conclusions The expression of adipokines in the sera of patients with MPA and GPA differs depending on clinical and laboratory features, and serum resistin may be suggested as a potential biomarker reflecting disease activity.

scholarly journals Serum heat shock protein 70 levels as a biomarker for inflammatory processes in multiple sclerosis

2018 ◽  
Vol 4 (2) ◽  
pp. 205521731876719 ◽  
Author(s):  
Patricia Lechner ◽  
Dorothea Buck ◽  
Lisa Sick ◽  
Bernhard Hemmer ◽  
Gabriele Multhoff
Keyword(s):  
Multiple Sclerosis ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Neurological Diseases ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Potential Biomarker ◽  
Inflammatory Processes

Background Inflammatory and neurodegenerative processes are hallmarks of multiple sclerosis (MS). The synthesis of the major stress-inducible heat shock protein 70 (Hsp70) is induced by inflammation. Objective The purpose of this study is to determine whether Hsp70 in serum can serve as a potential biomarker to distinguish inflammatory and neurodegenerative processes in MS. Methods Serum was obtained from 94 patients: 26 clinically isolated syndrome (CIS), 40 relapsing–remitting MS (RRMS), 19 secondary progressive MS (SPMS), and nine primary progressive MS (PPMS). As controls, serum samples were collected from patients with non-inflammatory neurological diseases (NINDs, n = 41), other inflammatory neurological diseases (OINDs, n = 28) and healthy donors (HDs, n = 114). Serum levels of Hsp70 were quantified using the enzyme-linked immunosorbent assay detecting free and liposomal Hsp70 (lipHsp70 ELISA). Results Patients with MS displayed significantly higher Hsp70 serum levels than HDs ( p < 0.001) and significantly lower levels than OINDs ( p = 0.001). A subgroup analysis revealed that Hsp70 serum levels of CIS/RRMS patients are significantly higher than those of patients with progressive MS (SPMS/PPMS) ( p < 0.05). Conclusion Inflammation causes the release of Hsp70 into the blood. As CIS/RRMS are associated with higher Hsp70 serum levels than progressive MS, serum Hsp70 levels might provide a marker for inflammatory processes.

scholarly journals The Application of a Three-Step Proteome Analysis for Identification of New Biomarkers of Pancreatic Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Mayinuer Abulaizi ◽  
Takeshi Tomonaga ◽  
Mamoru Satoh ◽  
Kazuyuki Sogawa ◽  
Kazuyuki Matsushita ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
High Performance ◽  
Binding Protein ◽  
Proteome Analysis ◽  
Serum Levels ◽  
Retinol Binding Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Two Dimensional Gel Electrophoresis ◽  
Retinol Binding Protein 4

We searched for novel tumor markers of pancreatic cancer by three-step serum proteome analysis. Twelve serum abundant proteins were depleted using immunoaffinity columns followed by fractionation by reverse-phase high-performance liquid chromatography. Proteins in each fraction were separated by two-dimensional gel electrophoresis. Then the gel was stained by Coomassie Brilliant Blue. Protein spots in which the expression levels were significantly different between cancer and normal control were identified by LC-MS/MS. One hundred and two spots were upregulated, and 84 spots were downregulated in serum samples obtained from patients with pancreatic cancers, and 58 proteins were identified by mass spectrometry. These candidate proteins were validated using western blot analysis and enzyme-linked immunosorbent assay (ELISA). As a result of these validation process, we could confirm that the serum levels of apolipoprotein A-IV, vitamin D-binding protein, plasma retinol-binding protein 4, and tetranectin were significantly decreased in patients with pancreatic cancer.

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