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Subject Item: _:vb39999542
rdf:type: n7:Section
dc:title: introduction
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Subject Item: _:vb39999543
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rdf:value: These subsets are maintained within niches which could facilitate cell-fate changes when necessary, underscoring the developmental plasticity of this population [>>3<<,4]. The prognostic significance of the cellular heterogeneity of neural crest lineage cells in NB has begun to be described [5,6]. Clinical evidence has recognized cell morphology diversity with the presence of a variety of neural crest
n5:mentions: n2:19089355

Subject Item: _:vb39999544
rdf:type: n5:Context
rdf:value: These subsets are maintained within niches which could facilitate cell-fate changes when necessary, underscoring the developmental plasticity of this population [3,>>4<<]. The prognostic significance of the cellular heterogeneity of neural crest lineage cells in NB has begun to be described [5,6]. Clinical evidence has recognized cell morphology diversity with the presence of a variety of neural crest
n5:mentions: n2:15917469

Subject Item: _:vb39999545
rdf:type: n5:Context
rdf:value: The prognostic significance of the cellular heterogeneity of neural crest lineage cells in NB has begun to be described [>>5<<,6]. Clinical evidence has recognized cell morphology diversity with the presence of a variety of neural crest cell types in neuroblastoma including neuroblasts, melanocytes, glial cells and chondrocytes [7,8]. Clonal sublines from such
n5:mentions: n2:6589432

Subject Item: _:vb39999546
rdf:type: n5:Context
rdf:value: The prognostic significance of the cellular heterogeneity of neural crest lineage cells in NB has begun to be described [5,>>6<<]. Clinical evidence has recognized cell morphology diversity with the presence of a variety of neural crest cell types in neuroblastoma including neuroblasts, melanocytes, glial cells and chondrocytes [7,8]. Clonal sublines from such
n5:mentions: n2:19156211

Subject Item: _:vb39999547
rdf:type: n5:Context
rdf:value: Clinical evidence has recognized cell morphology diversity with the presence of a variety of neural crest cell types in neuroblastoma including neuroblasts, melanocytes, glial cells and chondrocytes [>>7<<,8]. Clonal sublines from such neural crest cells identified three distinct types including: (1) small, rounded, loosely adherent cells with neurite-like processes, ‘N’ type cells; (2) large, flat, epithelial or fibroblast-like and highly
n5:mentions: n2:2445473

Subject Item: _:vb39999548
rdf:type: n5:Context
rdf:value: Clinical evidence has recognized cell morphology diversity with the presence of a variety of neural crest cell types in neuroblastoma including neuroblasts, melanocytes, glial cells and chondrocytes [7,>>8<<]. Clonal sublines from such neural crest cells identified three distinct types including: (1) small, rounded, loosely adherent cells with neurite-like processes, ‘N’ type cells; (2) large, flat, epithelial or fibroblast-like and highly
n5:mentions: n2:2888312

Subject Item: _:vb39999549
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rdf:value: Clinically, a higher percentage of I-type cells associated with augmented tumorigenicity as well as increased rates of tumor relapse [>>9<<]. Interestingly, these cells expressed CD133 and showed asymmetric cell division [9,10].
n5:mentions: n2:15720811

Subject Item: _:vb39999550
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rdf:value: Interestingly, these cells expressed CD133 and showed asymmetric cell division [>>9<<,10]. Other studies revealed that NB cells express neural precursor markers, including CD34, ABCG2 and nestin [11-13]. Sixty-five percent of primary NB samples have side populations, providing further evidence that NB is a stem cell tumor
n5:mentions: n2:15720811

Subject Item: _:vb39999551
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rdf:value: Interestingly, these cells expressed CD133 and showed asymmetric cell division [9,>>10<<]. Other studies revealed that NB cells express neural precursor markers, including CD34, ABCG2 and nestin [11-13]. Sixty-five percent of primary NB samples have side populations, providing further evidence that NB is a stem cell tumor
n5:mentions: n2:16839774

Subject Item: _:vb39999552
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rdf:value: Other studies revealed that NB cells express neural precursor markers, including CD34, ABCG2 and nestin [>>11<<-13]. Sixty-five percent of primary NB samples have side populations, providing further evidence that NB is a stem cell tumor [11]. Clinical and laboratory evidence suggests that several common human cancers contain populations of rapidly
n5:mentions: n2:15117961 n2:15811555 n2:15381773

Subject Item: _:vb39999553
rdf:type: n5:Context
rdf:value: Sixty-five percent of primary NB samples have side populations, providing further evidence that NB is a stem cell tumor [>>11<<]. Clinical and laboratory evidence suggests that several common human cancers contain populations of rapidly proliferating clonogens that can have a substantial impact on tumor control following therapy [14]. For many cancers, including
n5:mentions: n2:15381773

Subject Item: _:vb39999554
rdf:type: n5:Context
rdf:value: Clinical and laboratory evidence suggests that several common human cancers contain populations of rapidly proliferating clonogens that can have a substantial impact on tumor control following therapy [>>14<<]. For many cancers, including NB, it has been hypothesized that the tumor cells responsible for failures in long-term remission exhibit stem cell properties [15-21]. Since more than half of the patients with high-risk NB will relapse with
n5:mentions: n2:1509278

Subject Item: _:vb39999555
rdf:type: n5:Context
rdf:value: For many cancers, including NB, it has been hypothesized that the tumor cells responsible for failures in long-term remission exhibit stem cell properties [>>15<<-21]. Since more than half of the patients with high-risk NB will relapse with hematogenous metastasis [22] despite intensive multimodal therapy [23-32], we investigated the plasticity of stem-like aggressive NB cells. Plasticity is the
n5:mentions: n2:22438320 n2:23528862 n2:23616401 n2:22732500 n2:23104270 n2:23902339 n2:23784558

Subject Item: _:vb39999556
rdf:type: n5:Context
rdf:value: Since more than half of the patients with high-risk NB will relapse with hematogenous metastasis [>>22<<] despite intensive multimodal therapy [23-32], we investigated the plasticity of stem-like aggressive NB cells.
n5:mentions: n2:17586306

Subject Item: _:vb39999557
rdf:type: n5:Context
rdf:value: Since more than half of the patients with high-risk NB will relapse with hematogenous metastasis [22] despite intensive multimodal therapy [>>23<<-32], we investigated the plasticity of stem-like aggressive NB cells.
n5:mentions: n2:22427348 n2:21298742 n2:19616426 n2:20404250 n2:12847321 n2:8777176 n2:18429000 n2:15087949 n2:19171716

Subject Item: _:vb39999558
rdf:type: n5:Context
rdf:value: Adult neural crest-derived cells have been shown to retain stem cell properties [>>33<<]. Studies have consistently demonstrated that such neural crest stem cell (NCSC) populations often mimic transcription expression profiles of both embryonic stem cells and early neural crest cells [34-36].
n5:mentions: n2:19066583

Subject Item: _:vb39999559
rdf:type: n5:Context
rdf:value: Studies have consistently demonstrated that such neural crest stem cell (NCSC) populations often mimic transcription expression profiles of both embryonic stem cells and early neural crest cells [>>34<<-36]. Recent breakthrough investigations recognized the generation of induced pluripotent stem cells (iPSCs) [34,36] and showed that iPSCs can be derived by the manipulation of selective transcription factors. Given high-risk NB’s
n5:mentions: n2:16904174 n2:18157115 n2:19325077

Subject Item: _:vb39999560
rdf:type: n5:Context
rdf:value: Recent breakthrough investigations recognized the generation of induced pluripotent stem cells (iPSCs) [>>34<<,36] and showed that iPSCs can be derived by the manipulation of selective transcription factors.
n5:mentions: n2:18157115

Subject Item: _:vb39999561
rdf:type: n5:Context
rdf:value: Recent breakthrough investigations recognized the generation of induced pluripotent stem cells (iPSCs) [34,>>36<<] and showed that iPSCs can be derived by the manipulation of selective transcription factors.
n5:mentions: n2:19325077

Subject Item: _:vb39999562
rdf:type: n5:Context
rdf:value: Studies have shown the progression of solid tumors from a minor population of cancer stem cells (CSCs) with altered expression of selective molecules, self-renewal capacity, and differentiation [>>37<<]. These types of tumor cell subpopulations with altered stem-like phenotypes have been identified in several tumor systems, including leukemia, breast, brain and colon cancers [38-41]. Neuroblastoma CSCs that exhibit self-renewal and
n5:mentions: n2:23983818

Subject Item: _:vb39999563
rdf:type: n5:Context
rdf:value: These types of tumor cell subpopulations with altered stem-like phenotypes have been identified in several tumor systems, including leukemia, breast, brain and colon cancers [>>38<<-41]. Neuroblastoma CSCs that exhibit self-renewal and dynamic proliferation were also capable of generating non-adherent tumorospheres with enriched stemness [42]. Accordingly, we investigated the ongoing continuous modifications in the
n5:mentions: n2:9212098 n2:15549107 n2:17122772 n2:12629218

Subject Item: _:vb39999564
rdf:type: n5:Context
rdf:value: Neuroblastoma CSCs that exhibit self-renewal and dynamic proliferation were also capable of generating non-adherent tumorospheres with enriched stemness [>>42<<]. Accordingly, we investigated the ongoing continuous modifications in the stem cell-related transcriptional machinery of aggressive metastatic NB cells.
n5:mentions: n2:21114922

Subject Item: _:vb39999565
rdf:type: n7:Section
dc:title: methods
n7:contains: _:vb39999568 _:vb39999569 _:vb39999570 _:vb39999566 _:vb39999567

Subject Item: _:vb39999566
rdf:type: n5:Context
rdf:value: The parental human NB (SH-SY5Y) cell line obtained from ATCC (Manassas, VA, USA) was cultured and maintained as described earlier [>>43<<]. We maintained metastatic site-derived aggressive cell (MSDACs, Figure 1A) clones that were established from the manifold of metastatic tumors of a clinically mimicking animal model of human high-risk metastatic disease ex vivo in
n5:mentions: n2:21527635

Subject Item: _:vb39999567
rdf:type: n5:Context
rdf:value: Total RNA extraction and real-time QPCR profiling were performed as described earlier [>>44<<,45]. We used custom-made transcriptome profilers (Realtimeprimers.com) pertaining to stemness and EMT signaling.
n5:mentions: n2:22242139

Subject Item: _:vb39999568
rdf:type: n5:Context
rdf:value: Total RNA extraction and real-time QPCR profiling were performed as described earlier [44,>>45<<]. We used custom-made transcriptome profilers (Realtimeprimers.com) pertaining to stemness and EMT signaling.
n5:mentions: n2:21056117

Subject Item: _:vb39999569
rdf:type: n5:Context
rdf:value: Total protein extraction and immunoblotting were performed as described in our earlier studies [>>43<<,46]. In this study, the protein-transferred membranes were incubated with rabbit polyclonal anti-MYC, anti-Sox-2(Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), anti-ABGC2, and anti-nCadherin (Aviva Systems Biology Corp., San Diego,
n5:mentions: n2:21527635

Subject Item: _:vb39999570
rdf:type: n5:Context
rdf:value: Total protein extraction and immunoblotting were performed as described in our earlier studies [43,>>46<<]. In this study, the protein-transferred membranes were incubated with rabbit polyclonal anti-MYC, anti-Sox-2(Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), anti-ABGC2, and anti-nCadherin (Aviva Systems Biology Corp., San Diego, CA,
n5:mentions: n2:12201057

Subject Item: _:vb39999571
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dc:title: discussion
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Subject Item: _:vb39999572
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rdf:value: disease will disappear with spontaneous maturation or regression, while patients with stage 4 and 4 s disease present with hematogenous metastasis, relapse/recurrence after therapy, and experience a dramatic decline in overall survival [>>22<<,31,47]. Studies worldwide, including those from our laboratory, focus on identifying the molecular drivers that switch favorable neuroblastoma to high-risk metastatic disease.
n5:mentions: n2:17586306

Subject Item: _:vb39999573
rdf:type: n5:Context
rdf:value: will disappear with spontaneous maturation or regression, while patients with stage 4 and 4 s disease present with hematogenous metastasis, relapse/recurrence after therapy, and experience a dramatic decline in overall survival [22,>>31<<,47]. Studies worldwide, including those from our laboratory, focus on identifying the molecular drivers that switch favorable neuroblastoma to high-risk metastatic disease.
n5:mentions: n2:19616426

Subject Item: _:vb39999574
rdf:type: n5:Context
rdf:value: will disappear with spontaneous maturation or regression, while patients with stage 4 and 4 s disease present with hematogenous metastasis, relapse/recurrence after therapy, and experience a dramatic decline in overall survival [22,31,>>47<<]. Studies worldwide, including those from our laboratory, focus on identifying the molecular drivers that switch favorable neuroblastoma to high-risk metastatic disease.
n5:mentions: n2:21768459

Subject Item: _:vb39999575
rdf:type: n5:Context
rdf:value: Human cancers have been shown to contain populations of rapidly proliferating clonogens that can have a substantial impact on tumor control [>>14<<]. These tumor cells are responsible for failures in long-term remission and exhibit stem cell properties [15-21].
n5:mentions: n2:1509278

Subject Item: _:vb39999576
rdf:type: n5:Context
rdf:value: These tumor cells are responsible for failures in long-term remission and exhibit stem cell properties [>>15<<-21]. Conceptually, CSCs, a small subset of cells, constitute a reservoir of self-sustaining cells with the exclusive ability to self-renew and to spawn the heterogeneous lineages of cancer cells that comprise the tumor [48]. Emerging
n5:mentions: n2:22438320 n2:23528862 n2:22732500 n2:23104270 n2:23616401 n2:23784558 n2:23902339

Subject Item: _:vb39999577
rdf:type: n5:Context
rdf:value: Conceptually, CSCs, a small subset of cells, constitute a reservoir of self-sustaining cells with the exclusive ability to self-renew and to spawn the heterogeneous lineages of cancer cells that comprise the tumor [>>48<<]. Emerging evidence from multiple tumor systems, including neuroblastoma, recognizes the driving role of such CSCs in tumor progression, relapse, recurrence, and poor clinical outcomes [49-51]. Researchers have postulated the
n5:mentions: n2:22430387

Subject Item: _:vb39999578
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rdf:value: Emerging evidence from multiple tumor systems, including neuroblastoma, recognizes the driving role of such CSCs in tumor progression, relapse, recurrence, and poor clinical outcomes [>>49<<-51]. Researchers have postulated the unidirectional and bi-directional plasticity of these CSCs and highlighted their significance in tumor progression events [52,53]. In the current study, we examined the reversible and intrinsic
n5:mentions: n2:22588778 n2:23890779 n2:22862175

Subject Item: _:vb39999579
rdf:type: n5:Context
rdf:value: Researchers have postulated the unidirectional and bi-directional plasticity of these CSCs and highlighted their significance in tumor progression events [>>52<<,53]. In the current study, we examined the reversible and intrinsic adaptive plasticity of the human neuroblastoma MSDACs derived from clinically mimicking and translatable spontaneous high-risk metastatic tumors.
n5:mentions: n2:23220226

Subject Item: _:vb39999580
rdf:type: n5:Context
rdf:value: Researchers have postulated the unidirectional and bi-directional plasticity of these CSCs and highlighted their significance in tumor progression events [52,>>53<<]. In the current study, we examined the reversible and intrinsic adaptive plasticity of the human neuroblastoma MSDACs derived from clinically mimicking and translatable spontaneous high-risk metastatic tumors.
n5:mentions: n2:24048065

Subject Item: _:vb39999581
rdf:type: n5:Context
rdf:value: These data validate the conceptual hypothesis that aggressive metastatic cells exhibit stem cell properties [>>15<<-21]. Utilizing validated human MSDACs that characteristically fit the CSC model to elucidate and typify plasticity allows us to closely relate these outcomes to clinical settings. Despite extensive neuroblastoma research recognizing the
n5:mentions: n2:22438320 n2:23528862 n2:22732500 n2:23104270 n2:23616401 n2:23784558 n2:23902339

Subject Item: _:vb39999582
rdf:type: n5:Context
rdf:value: Chakrabarti and colleagues demonstrated the reversible plasticity of neuroblastoma cells [>>54<<] and further recognized the mechanism linking Id2 and TGFβ in drug-associated adaptive plasticity [55].
n5:mentions: n2:22891161

Subject Item: _:vb39999583
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rdf:value: Chakrabarti and colleagues demonstrated the reversible plasticity of neuroblastoma cells [54] and further recognized the mechanism linking Id2 and TGFβ in drug-associated adaptive plasticity [>>55<<]. Consistently, our results demonstrated and validated the reversible plasticity in neuroblastoma cells. For the first time, this study explained neuroblastoma cells’ phenotype switching in MSDACs that typically fit the CSC model.
n5:mentions: n2:24376712

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