TAMI-28. IDENTIFICATION OF A NEUROLIGIN-3 BINDING PARTNER IN HIGH-GRADE GLIOMAS AND NORMAL PROGENITORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi204-vi204
Author(s):  
Shawn Gillespie ◽  
Yoon Seok Kim ◽  
Anna Geraghty ◽  
Michael Quezada ◽  
James Reed ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Glioma Cells ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Size Exclusion ◽  
Dependent Manner ◽  
High Grade ◽  
Gamma Secretase ◽  
Binding Partner ◽  
High Grade Gliomas

Abstract High-grade gliomas, including diffuse intrinsic pontine glioma, are lethal cancers whose progression is strongly regulated by neuronal activity. One way in which gliomas detect neuronal activity is via interaction with the ectodomain of post-synaptic adhesion protein neuroligin-3 (NLGN3), which is shed from neurons and oligodendrocyte precursors (OPCs) by the ADAM10 sheddase in an activity dependent manner. NLGN3 signaling drives glioma growth, but the cognate binding partner of shed NLGN3 (sNLGN3) on glioma cells is unknown. Here, we employed a proximity labeling technique to identify chondroitin sulfate proteoglycan 4 (CSPG4) as a putative binding partner of sNLGN3 in gliomas. We then confirmed complexing between recombinant proteins with size exclusion chromatography and are determining kinetics and affinity by surface plasmon resonance. When looking for evidence of binding in cells, we were surprised to find that sNLGN3 triggers regulated intramembrane proteolysis (RIP) of CSPG4, leaving no trace of the interaction at the membrane. sNLGN3 binding first induces ADAM10-mediated cleavage and release of the CSPG4 ectodomain, followed by gamma secretase-mediated release of the intracellular domain and downstream signaling in OPCs and gliomas. Pre-treatment of glioma cells or OPCs with an ADAM10 inhibitor entirely blocks sNLGN3-induced CSPG4 shedding. Acute depletion of CSPG4 via CRISPR gene editing renders glioma cells insensitive to the growth-promoting effects of sNLGN3 in vitro. Furthermore, we find that tamoxifen-induced deletion of NLGN3 from murine OPCs reduces the total number of OPCs, suggesting that this signaling axis promotes maintenance of OPC stemness in an autocrine fashion. Indeed, gamma secretase inhibition accelerates OPC differentiation in vitro, pointing towards a fundamental role for sNLGN3-CSPG4 signaling in OPCs and high-grade gliomas. Altogether, our results form a critical missing link in understanding how glioma cells detect a key neuronal activity-regulated signal, suggest intriguing links to OPC biology and identify a therapeutic target to disrupt neuron-glioma interactions.

scholarly journals HGG-05. NEURONAL ACTIVITY PROMOTES PEDIATRIC HIGH-GRADE GLIOMA GROWTH THROUGH A NLGN3-CSPG4 SIGNALING AXIS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i18-i18
Author(s):  
Shawn Gillespie ◽  
Yoon Kim ◽  
Anna Geraghty ◽  
Pamelyn Woo ◽  
Michelle Monje
Keyword(s):  
Neuronal Activity ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
High Grade ◽  
Gamma Secretase ◽  
Intracellular Domain ◽  
Glioma Growth ◽  
Pre Treatment

Abstract High-grade gliomas, including diffuse intrinsic pontine glioma (DIPG), are a lethal group of cancers whose progression is strongly regulated by neuronal activity {Venkatesh 2015}{Venkatesh 2017}{Venkatesh 2019}. One way in which glioma cells sense neuronal activity is via interaction with the ectodomain of post-synaptic adhesion protein neuroligin-3 (NLGN3), which is cleaved and released into the tumor microenvironment (TME) by the sheddase ADAM10. This interaction drives glioma growth, but the relevant binding partner of shed NLGN3 (sNLGN3) on glioma cells is currently unknown. Here, we report that sNLGN3 binds to chondroitin sulfate proteoglycan 4 (CSPG4), in turn inducing regulated intramembrane proteolysis (RIP) of CSPG4, and initiating a signaling cascade within DIPG cells to promote tumor growth. CSPG4 RIP involves activity-regulated ectodomain shedding by ADAM10 and subsequent gamma secretase-mediated release of the intracellular domain in healthy oligodendroglial precursor cells (OPCs), putative cells of origin for several forms of high-grade glioma {Sakry 2014}{Nayak 2018}. Incubation of high-grade glioma cells or healthy OPCs with recombinant NLGN3 is sufficient to augment ADAM10-mediated ectodomain release of CSPG4 and subsequent gamma secretase-mediated cleavage of the CSPG4 intracellular domain (ICD). Pre-treatment of glioma cells or OPCs with an ADAM10 inhibitor entirely blocks NLGN3-induced CSPG4 shedding. Acute depletion of CSPG4 via CRISPR gene editing renders glioma cells insensitive to the growth-promoting effects of NLGN3 application in vitro. We are now performing experiments to better discern how the CSPG4 ICD regulates signaling consequences downstream of sNLGN3 binding. In addition, we are using surface plasmon resonance to investigate whether the shed ectodomains of NLGN3 and CSPG4 remain in complex or only transiently interact. Altogether, our data form a critical missing link in understanding how glioma cells sense, translate and respond to neuronal activity in the TME and identify a new therapeutic target to disrupt neuron-glioma interactions.

scholarly journals Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance

2015 ◽  
Vol 122 (6) ◽  
pp. 1360-1369 ◽  
Author(s):  
Roberto Jose Diaz ◽  
Roberto Rey Dios ◽  
Eyas M. Hattab ◽  
Kelly Burrell ◽  
Patricia Rakopoulos ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Low Dose ◽  
Glioma Cells ◽  
High Grade ◽  
Fluorescein Sodium ◽  
Tumor Margins ◽  
Histopathological Correlation ◽  
High Grade Gliomas

OBJECT Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell–specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI–guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.

scholarly journals H3.3K27M Mutation Promotes The Migration and Invasion of Glioma Cells By Activating β-Catenin/USP1 Signaling

2022 ◽  
Author(s):  
Zhiyuan Sun ◽  
Yufu Zhu ◽  
Xia Feng ◽  
Xiaoyun Liu ◽  
Kunlin Zhou ◽  
...  
Keyword(s):  
Glioma Cells ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
High Grade ◽  
Protein Levels ◽  
Adult Glioma

Abstract H3.3K27M is a newly identified molecular pathology marker in glioma and is especially correlated with the malignancy of diffuse intrinsic pontine glioma (DIPG). In recent years, accumulating research has revealed that other types of glioma also contain the H3.3K27M mutation. However, the role of H3.3K27M in high-grade adult glioma, which is the most malignant glioma, has not been investigated. In this study, we focused on exploring the expression and function of H3.3K27M in high-grade adult glioma patients. We found that H3.3K27M is partly highly expressed in high-grade glioma tissues. Then, we introduced H3.3K27M into H3.3 wild-type glioma cells, U87 cells and LN229 cells. We found that H3.3K27M did not regulate the growth of glioma in vitro and in vivo; however, the survival of mice with transplanted tumors was significantly reduced. Further investigation revealed that H3.3K27M expression mainly promoted the migration and invasion of glioma cells. Moreover, we certified that H3.3K27M overexpression enhanced the protein levels of ꞵ-catenin and p-ꞵ-catenin, the protein and mRNA levels of ubiquitin-specific protease 1 (USP1), and the protein level of enhancer of zeste homolog 2 (EZH2). Importantly, the ꞵ-catenin inhibitor XAV-939 significantly attenuated the upregulation of the aforementioned proteins. Overall, the H3.3K27M mutation is present in a certain proportion of high-grade glioma patients and facilitates a poor prognosis by promoting the metastasis of glioma by regulating the ꞵ-catenin/USP1/EZH2 pathway.

Synergistic Apoptotic Effect of Naringenin on enhancing the Anti-Glioma Efficacy of Temozolomide in an in vitro Experimental Model

2021 ◽  
Vol 16 (10) ◽  
pp. 43-49
Author(s):  
Precilla S. Daisy ◽  
S. Kuduvalli Shreyas ◽  
R. Sathish ◽  
T.S. Anitha
Keyword(s):  
Drug Treatment ◽  
Caspase 3 ◽  
Treatment Strategies ◽  
Glioma Cells ◽  
C6 Glioma ◽  
Mitigation Strategies ◽  
Treatment Modalities ◽  
C6 Glioma Cells ◽  
Dependent Manner

Glioma is one of the most devastating and difficult-totreat brain tumors with a very poor prognosis. Despite the current treatment modalities, the overall survival rate is only 5% contributing to a high mortality rate. Nevertheless, of emerging treatment strategies, there is still a rising need for novel mitigation strategies to counteract glioma aggressiveness. One attempt towards this long-term goal was made in this study to reveal the combined efficacy of naringenin, a bioactive flavonoid on enhancing the anti-glioma potency of temozolomide in C6 glioma cells. The cytotoxic effect of temozolomide and naringenin, both individually and in combination was assessed by employing MTT assay. The synergistic effect of the drugs temozolomide and naringenin was determined by calculating the combination index. To confirm the presence of apoptotic changes in the cells at morphological level, acridine orange/ethidium bromide staining was performed. Further, the modulatory effects of the drugs on apoptotic genes, caspase-3 and BCL-2 were evaluated using quantitative real time-PCR. Interestingly, we found that the combinatorial drug treatment was in consensus and effectively inhibited the growth of C6 glioma cells in a dose-dependent manner. Furthermore, this combinatorial drug treatment significantly up-regulated the expression of the proapoptotic gene, caspase-3 and down-regulated the anti-apoptotic gene BCL-2 suggesting a shift of equilibrium towards apoptosis. Our findings suggest that naringenin can be employed as a potent drug to enhance the anti-glioma efficacy of temozolomide and could be therapeutically exploited for the management of glioma.

scholarly journals Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

2021 ◽  
Author(s):  
Xuyang Lv ◽  
Jiangchuan Sun ◽  
Linfeng Hu ◽  
Ying Qian ◽  
Chunlei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

scholarly journals Inhibitory effect of schizophyllan on rat glioma cells

2015 ◽  
Vol 10 (4) ◽  
pp. 759 ◽  
Author(s):  
Bin Zhou ◽  
Qiang Fu ◽  
Sha-Sha Song ◽  
Hong-Li Zheng ◽  
Yu-Zhen Wei
Keyword(s):  
Cell Cycle ◽  
Propidium Iodide ◽  
Experimental Studies ◽  
Glioma Cells ◽  
Annexin V ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Rat Glioma ◽  
Rat Cns

<p class="Abstract">The aim of this study was to examine the anticancer effects of schizophyllan (a -D-glucan) against the growth of rat CNS-1 glioma cells and preliminarily assess its effect on inducing apoptosis and blocking cell cycle. In order to evaluate its inhibitory effect, firstly MTT assay was conducted followed by annexin V/propidium iodide double staining or propidium iodide single staining, apoptosis and cell cycle using flow cytometry. All the experiments were carried in a dose- and time-dependent manner. Experimental results showed that treatment of 40 and 60 mg/L schizophyllan significantly increa-sed the apoptotic rate and blocked the cell cycle. In addition, increase in the proportion of cells in G0/G1 phase and decrease in the proportion of S-phase cells were also observed. Overall experimental studies suggest that schizo-phyllan can significantly inhibit the growth of rat CNS-1 glioma cells, in vitro and induced apoptosis and blocked the cell cycle.</p><p> </p>

scholarly journals CSIG-31. ALTERNATIVE RECEPTOR TYROSINE KINASE SIGNALING AS A RESISTANCE MECHANISM TO ERK INHIBITION IN HIGH-GRADE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi50-vi51
Author(s):  
Ann-Catherine Stanton ◽  
Robert Koncar ◽  
Brian Golbourn ◽  
Michelle Wassell ◽  
Nishant Agrawal ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Protein Level ◽  
Resistance Mechanisms ◽  
Kinase Domain ◽  
High Grade ◽  
Transactivation Domain ◽  
Tyrosine Kinase 2 ◽  
High Grade Gliomas

Abstract Pediatric High-Grade Gliomas (PHGG), which include Diffuse Midline Gliomas (DMG), are a leading cause of brain tumor death in children. Our recent work has identified extracellular signal-regulated kinase 5 (ERK5) as a critical mediator of cell survival in PHGG. Suppression of ERK5 genetically or pharmacologically leads to decreased cell proliferation and increased apoptosis both in vitro and in vivo in multiple PHGG and H3K27M mutant DMG cell lines. Mechanistically, we show that ERK5 directly stabilizes the proto-oncogene MYC at the protein level, providing rationale to clinically target ERK5. ERK5 contains both a kinase domain (KD) and a transactivation domain (TAD), unlike all other ERKs. Unexpectedly, we found that our ERK5 depleted cells could be partially rescued by an ERK5 kinase domain dead (ERK5-KDD) but TAD intact construct. Additionally, persistent ERK5 depletion does not result in complete growth inhibition and therefore we set out to determine potential adaptation or resistance mechanisms in response to ERK5 loss. To address this, we performed RNA sequencing of DMG cells, comparing control cells to ERK5 knockdown cells, and performed gene-ontology (GO) pathway analysis to identify transcriptional changes that occur in response to ERK5 depletion. We identified 105 differentially expressed genes, and GO analysis identified alternative receptor tyrosine kinase (RTK) gene-expression as one of the top biological processes upregulated in response to ERK5 loss. We validated our top targets at the RNA and the protein level. Our top targets were Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) and Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), both clinically actionable targets. Our future work will focus on functional validation of these RTKs as potential resistance mechanisms to ERK5 loss. Identification of resistance mechanisms to ERK5 loss will have both biological and translational relevance and may lead to effective therapeutic combinations.

scholarly journals CBMT-48. TARGETING METABOLIC REPROGRAMMING WITH NANOCURCUMIN IN GLIOBLASTOMA MULTIFORME

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi43-vi43
Author(s):  
Hamid Suhail ◽  
Rattan Ramandeep ◽  
Giri Shailendra ◽  
Ana deCarvalho ◽  
Steven Kalkanis ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Water Solubility ◽  
Curcuma Longa ◽  
Glioma Cells ◽  
Metabolic Reprogramming ◽  
Dependent Manner ◽  
Systemic Delivery ◽  
Ampk Activity

Abstract Glioblastoma (GBM) is a highly glycolytic aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. AMPK has been reported as tumor suppressor and reprograms the cellular metabolic pathways and produces a metabolic checkpoint on the cell cycle though mTORC1, p53 and other modulators involved in cell proliferation, growth, survival and autophagy. The AMPK activity is diminished in gastric, breast and ovarian tumor cells by activated PI3K-AKT pathways. Cancer cells are able to reprogram their energy metabolism to compensate their high bioenergetic demands needed for their aggressive growth and survival. Curcumin exhibits pleiotropic properties and activate MAPK and leads to suppress p53, Wnt/β-catenin, SHH and PI3K-AKT signaling pathways. Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). The absorption, biodistribution, metabolism, and elimination studies of curcumin have, unfortunately, shown only poor absorption, rapid metabolism, and elimination of curcumin as major reasons for poor bioavailability of this interesting polyphenolic compound. We have engineered a curcumin-based nanoparticle (Curc-NP) which demonstrates high water solubility. Curc-NP was effectively transported into the cells by nanoparticles through endocytosis and localized around the nuclei in the cytoplasms. In vitro studies proved that the cytotoxicity of Curc-NP is more effective against U-251 cell line in a dose-dependent manner. Systemic delivery of Curc-NP led to preferentially accumulation in an orthotopic preclinical glioma model minimizing systemic toxic effect. Multicolor microscopy images of the tumor tissue showed that Curc-NP particles were internalized inside tumor cells selectively and localized within nuclei. Curc-NP demonstrated to restore the dysregulated AMPK activity in glioma cells. Curc-NP-induced AMPK activation resulted in inhibition of oncogenic signalling pathways in glioma. Curc-NP-induced metabolic reprograming in glioma cells will be examined and the in vivo therapeutic efficacy of Curc-NP in an experimental rat model of GBM will also be evaluated.

Hypoxia-inducible factor 1α in regulation of programmed death: Ligand 1 in glioma under hypoxia microenvironment.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 103-103
Author(s):  
Man Hu ◽  
Song Xue ◽  
Jinming Yu ◽  
Bingjie Fan ◽  
Ji Ma ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Survival Time ◽  
Immune Escape ◽  
Hypoxia Inducible Factor ◽  
High Grade ◽  
Programmed Death Ligand 1 ◽  
Hypoxia Inducible Factor 1Α ◽  
Programmed Death ◽  
High Grade Gliomas

103 Background: Glioma is a highly lethal tumor that is known for its immune inhibitory capabilities. Despite great progress in treatment modalities, the median survival time of high-grade gliomas patients is only about 11.1 months. Gliomas are aberrantly expressed programmed death–ligand 1 (PD-L1) which results in tumor-induced immune suppression. Hypoxia is well known to induce aggressiveness, promotes tumor progression and resistance to chemotherapy and radiotherapy. Recently, studies have indicated that hypoxia play a prominent role in tumor immune escape. The aim of the study was to explore the relationship between PD-L1 and hypoxia inducible factor 1α (HIF-1α) and the role in the progression of gliomas. Methods: We adopted immunohistochemistry methods to detect expressions of PD-L1 and HIF-1α in 64 surgical specimens (23 cases for low-grade and 41 cases for high-grade gliomas, respectively). Immunoreactivity was analyzed in association with patients’ clinical characteristics or survival time. Expression of the PD-L1 and HIF-1α was analyzed in three GBM cell lines, U343, U373, and U251, under in vitro hypoxia (12, 24 or 72 h at 0.1% O2). Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out to detect the mRNA expression of PD-L1 and HIF-1α. Results: PD-L1 and HIF-1α protein expression was detected in 81.25% and 84.73% of glioma specimens, respectively. The expression of PD-L1 protein is positively correlated with HIF-1α (r = 0.52; p= 0.013). Kaplan–Meier analysis revealed a significant effect of PD-L1 grade on cumulative overall survival. Patients with negative PD-L1 expression survive longer than those with positive expression ( p= 0.007). PD-L1 and HIF-1α mRNA was most consistently upregulated in relation to duration of in-vitro hypoxia (72h, p= 0.007). There was a significant and positive relationship between the PD-L1 and HIF-1α mRNA expression (r = 0.45; p= 0.01). Conclusions: The present study showed a role for hypoxia/HIF-1α in driving immune escape and provided a potential novel cancer immunotherapy targeting hypoxia to block PD-L1 expression, which may boost the immune system in cancer patients.

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