@prefix rdf: . @prefix ns1: . rdf:type ns1:CitationPaper , ns1:RelevantPaper , ns1:ReferencePaper . @prefix rdfs: . rdfs:seeAlso , , . @prefix bibo: . bibo:cites , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; ns1:cocitationWith , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; ns1:hasRelevantBibliographicResourceOf _:b567468988 , _:b567468989 , _:b567468990 , _:b567468991 , _:b567468985 , _:b567468986 , _:b567468987 , _:b567469028 , _:b567469029 , _:b567469030 , _:b567469031 , _:b567469024 , _:b567469025 , _:b567469026 , _:b567469027 , _:b567469036 , _:b567469037 , _:b567469038 , _:b567469039 , _:b567469032 , _:b567469033 , _:b567469034 , _:b567469035 , _:b567469044 , _:b567469045 , _:b567469046 , _:b567469047 , _:b567469040 , _:b567469041 , _:b567469042 , _:b567469043 , _:b567469052 , _:b567469053 , _:b567469054 , _:b567469055 , _:b567469048 , _:b567469049 , _:b567469050 , _:b567469051 , _:b567468996 , _:b567468997 , _:b567468998 , _:b567468999 , _:b567468992 , _:b567468993 , _:b567468994 , _:b567468995 , _:b567469004 , _:b567469005 , _:b567469006 , _:b567469007 , _:b567469000 , _:b567469001 , _:b567469002 , _:b567469003 , _:b567469012 , _:b567469013 , _:b567469014 , _:b567469015 , _:b567469008 , _:b567469009 , _:b567469010 , _:b567469011 , _:b567469020 , _:b567469021 , _:b567469022 , _:b567469023 , _:b567469016 , _:b567469017 , _:b567469018 , _:b567469019 , _:b567469092 , _:b567469093 , _:b567469094 , _:b567469095 , _:b567469088 , _:b567469089 , _:b567469090 , _:b567469091 , _:b567469100 , _:b567469101 , _:b567469102 , _:b567469103 , _:b567469096 , _:b567469097 , _:b567469098 , _:b567469099 , _:b567469108 , _:b567469109 , _:b567469104 , _:b567469105 , _:b567469106 , _:b567469107 , _:b567469060 , _:b567469061 , _:b567469062 , _:b567469063 , _:b567469056 , _:b567469057 , _:b567469058 , _:b567469059 , _:b567469068 , _:b567469069 , _:b567469070 , _:b567469071 , _:b567469064 , _:b567469065 , _:b567469066 , _:b567469067 , _:b567469076 , _:b567469077 , _:b567469078 , _:b567469079 , _:b567469072 , _:b567469073 , _:b567469074 , _:b567469075 , _:b567469084 , _:b567469085 , _:b567469086 , _:b567469087 , _:b567469080 , _:b567469081 , _:b567469082 , _:b567469083 ; ns1:pmcid "PMC0" . @prefix ns4: . ns4:contains _:b36443767 , _:b36443775 , _:b36443782 , _:b36443790 . _:b36443767 rdf:type ns4:Section . @prefix dc: . _:b36443767 dc:title "introduction" ; ns4:contains _:b36443768 , _:b36443769 , _:b36443770 , _:b36443771 , _:b36443772 , _:b36443773 , _:b36443774 . _:b36443768 rdf:type ns1:Context ; rdf:value "Pancreatic cancer is among the most intractable of all human cancers and is also a leading cause of cancer-related death in the world [>>1<<, 2]. Besides the difficulty of early detection, which leads to dismally low surgical resection rate, pancreatic cancer is characterized by pervasive therapy resistance, being refractory to both chemotherapy and radiotherapy [3\u20135]." ; ns1:mentions . _:b36443769 rdf:type ns1:Context ; rdf:value "Pancreatic cancer is among the most intractable of all human cancers and is also a leading cause of cancer-related death in the world [1, >>2<<]. Besides the difficulty of early detection, which leads to dismally low surgical resection rate, pancreatic cancer is characterized by pervasive therapy resistance, being refractory to both chemotherapy and radiotherapy [3\u20135]." ; ns1:mentions . _:b36443770 rdf:type ns1:Context ; rdf:value "Besides the difficulty of early detection, which leads to dismally low surgical resection rate, pancreatic cancer is characterized by pervasive therapy resistance, being refractory to both chemotherapy and radiotherapy [>>3<<\u20135]. In the past decades, the survival of patients with pancreatic cancer has been improved with the development of fluorouracil (FU)- and gemcitabine (GEM)-based chemotherapeutic regimens, however, the prognosis of pancreatic cancer still" ; ns1:mentions , , . _:b36443771 rdf:type ns1:Context ; rdf:value "improved with the development of fluorouracil (FU)- and gemcitabine (GEM)-based chemotherapeutic regimens, however, the prognosis of pancreatic cancer still remains miserably poor with only less than 10% of patients surviving 5 years [>>5<<\u20137]." ; ns1:mentions , , . _:b36443772 rdf:type ns1:Context ; rdf:value "been associated with higher therapy resistance compared with non-stem cancer cells and are therefore increasingly deemed a major culprit of post-treatment progression and/or recurrence of a variety of, albeit not all, human cancers [>>8<<\u201312]. Since the identification of pancreatic CSCs, studies have consistently shown that pancreatic CSCs do have higher chemoresistance than non-stem pancreatic cancer cells and have also implicated pancreatic CSCs in the poor prognosis of" ; ns1:mentions , , , . _:b36443773 rdf:type ns1:Context ; rdf:value "CSCs in the poor prognosis of pancreatic cancer, suggesting that overcoming the chemoresistance inherently associated with pancreatic CSCs is apparently an indispensible step to improve overall management of pancreatic cancer [>>13<<, 14]. However, to date, the molecular basis on which pancreatic CSCs acquire resistance to conventional chemotherapeutic agents against pancreatic cancer has been poorly understood." ; ns1:mentions . _:b36443774 rdf:type ns1:Context ; rdf:value "CSCs in the poor prognosis of pancreatic cancer, suggesting that overcoming the chemoresistance inherently associated with pancreatic CSCs is apparently an indispensible step to improve overall management of pancreatic cancer [13, >>14<<]. However, to date, the molecular basis on which pancreatic CSCs acquire resistance to conventional chemotherapeutic agents against pancreatic cancer has been poorly understood." ; ns1:mentions . _:b36443775 rdf:type ns4:Section ; dc:title "materials and methods" ; ns4:contains _:b36443776 , _:b36443777 , _:b36443778 , _:b36443779 , _:b36443780 , _:b36443781 . _:b36443776 rdf:type ns1:Context ; rdf:value "The establishment of PANC-1 CSLCs and PSN-1 CSLCs, CSCs derived from human pancreatic cancer cell lines PANC-1 and PSN-1, respectively, was previously reported [>>15<<]. The authenticity of PANC-1 CSLCs and PSN-1 CSLCs as cells derived from PANC-1 and PSN-1, respectively, was verified by genotyping of short tandem repeat (STR) loci (Bio-Synthesis, Inc., Lewisville, TX, USA) followed by comparison to the" ; ns1:mentions . _:b36443777 rdf:type ns1:Context ; rdf:value "Unless otherwise indicated, these pancreatic CSCs were stably maintained and used for experiments under the monolayer stem cell culture condition, as previously described [>>15<<]. Briefly, cells were cultured on collagen-I-coated dishes (IWAKI, Tokyo, Japan) in the stem cell culture medium (DMEM/F12 medium supplemented with 1% B27 [Gibco-BRL, Carlsbad, CA, USA], 20 ng/mL EGF and FGF2 [Peprotech, Inc., Rocky Hill," ; ns1:mentions . _:b36443778 rdf:type ns1:Context ; rdf:value "Differentiation of pancreatic CSCs was induced by culturing the cells under the differentiation-inducing condition (DMEM/F12 containing 10% FBS) for 2 weeks, as previously described [>>15<<]. Normal human IMR90 fetal lung fibroblasts [46, 47] were obtained from American Type Culture Collection and maintained in DMEM/F12 supplemented with 10% fetal bovine serum (FBS) and 100 units/mL penicillin and 100 \u03BCg/mL streptomycin. All" ; ns1:mentions . _:b36443779 rdf:type ns1:Context ; rdf:value "Normal human IMR90 fetal lung fibroblasts [>>46<<, 47] were obtained from American Type Culture Collection and maintained in DMEM/F12 supplemented with 10% fetal bovine serum (FBS) and 100 units/mL penicillin and 100 \u03BCg/mL streptomycin." ; ns1:mentions . _:b36443780 rdf:type ns1:Context ; rdf:value "Normal human IMR90 fetal lung fibroblasts [46, >>47<<] were obtained from American Type Culture Collection and maintained in DMEM/F12 supplemented with 10% fetal bovine serum (FBS) and 100 units/mL penicillin and 100 \u03BCg/mL streptomycin." ; ns1:mentions . _:b36443781 rdf:type ns1:Context ; rdf:value "Viable and dead cells were identified by their ability and inability to exclude vital dyes, respectively [>>48<<]. In brief, cells were stained with 0.2% trypan blue, and the numbers of viable and dead cells were determined using a hemocytometer. Cell viability (%) was defined as 100 \u00D7 \u2018the number of viable cells\u2019/ (\u2018the number of viable cells\u2019 +" ; ns1:mentions . _:b36443782 rdf:type ns4:Section ; dc:title "results" ; ns4:contains _:b36443788 , _:b36443789 , _:b36443784 , _:b36443785 , _:b36443786 , _:b36443787 , _:b36443783 . _:b36443783 rdf:type ns1:Context ; rdf:value "CSCs are in general considered to be highly resistant to chemotherapeutic drugs [>>9<<, 10]. To examine whether this applies to the pancreatic CSCs we have established, we used PANC-1 CSLCs, CSCs derived from the pancreatic cancer cell line PANC-1 [15], and determined the sensitivity of self-renewing (undifferentiated)" ; ns1:mentions . _:b36443784 rdf:type ns1:Context ; rdf:value "CSCs are in general considered to be highly resistant to chemotherapeutic drugs [9, >>10<<]. To examine whether this applies to the pancreatic CSCs we have established, we used PANC-1 CSLCs, CSCs derived from the pancreatic cancer cell line PANC-1 [15], and determined the sensitivity of self-renewing (undifferentiated) PANC-1" ; ns1:mentions . _:b36443785 rdf:type ns1:Context ; rdf:value "To examine whether this applies to the pancreatic CSCs we have established, we used PANC-1 CSLCs, CSCs derived from the pancreatic cancer cell line PANC-1 [>>15<<], and determined the sensitivity of self-renewing (undifferentiated) PANC-1 CSLCs and their serum-differentiated counterparts to 5-FU and GEM, which are current chemotherapeutic agents of choice for the treatment of pancreatic cancer." ; ns1:mentions . _:b36443786 rdf:type ns1:Context ; rdf:value "We then conducted similar analyses using PSN-1 CSLCs, CSCs derived from another pancreatic cancer cell line PSN-1 [>>15<<]. The results indicated that the IC50 values of 5-FU and GEM for self-renewing PSN-1 CSLCs were again much higher than those for their differentiated counterparts [5-FU: approximately 1 \u03BCM and 0.3 \u03BCM for self-renewing and differentiated" ; ns1:mentions . _:b36443787 rdf:type ns1:Context ; rdf:value "We have recently demonstrated that the JNK signaling pathway is activated in self-renewing pancreatic CSCs compared with their differentiated counterparts [>>15<<]. Because our present data indicated that self-renewing pancreatic CSCs were more resistant to 5-FU and GEM (Figure 1; Supplementary Figure 1), we questioned whether JNK signaling is involved in the chemoresistance of pancreatic CSCs to" ; ns1:mentions . _:b36443788 rdf:type ns1:Context ; rdf:value "Since reactive oxygen species (ROS) have been implicated in the cytotoxicity of chemotherapeutic agents such as 5-FU and GEM [>>16<<\u201321], we examined the intracellular ROS levels of pancreatic CSCs after drug treatment." ; ns1:mentions , , , , , . _:b36443789 rdf:type ns1:Context ; rdf:value "has a role in SP600125-mediated sensitization of PANC-1 CSLCs to 5-FU and GEM, we next examined the effect of the antioxidant N-acetylcysteine (NAC), which scavenges free radicals by increasing intracellular glutathione levels (GSH) [>>22<<]. NAC, which effectively suppressed the increase in intracellular ROS, inhibited sensitization of pancreatic CSCs to 5-FU and GEM by SP600125; NAC treatment significantly decreased the proportion of dead cells after treatment of PANC-1" ; ns1:mentions . _:b36443790 rdf:type ns4:Section ; dc:title "discussion" ; ns4:contains _:b36443804 , _:b36443805 , _:b36443806 , _:b36443807 , _:b36443800 , _:b36443801 , _:b36443802 , _:b36443803 , _:b36443796 , _:b36443797 , _:b36443798 , _:b36443799 , _:b36443792 , _:b36443793 , _:b36443794 , _:b36443795 , _:b36443791 , _:b36443808 , _:b36443809 , _:b36443810 , _:b36443811 . _:b36443791 rdf:type ns1:Context ; rdf:value "Pancreatic cancer is one of the most malignant human cancers, which is so often unresectable already at the time of diagnosis and, above all, responds poorly to either chemotherapy or radiotherapy [>>3<<\u20135]. A growing body of evidence has come to suggest that pancreatic CSCs, endowed with both tumor-initiating capacity as well as with high therapy resistance, is among the key factors underlying the extreme refractoriness of pancreatic" ; ns1:mentions , , . _:b36443792 rdf:type ns1:Context ; rdf:value "Here in this study, we first found that pancreatic CSCs, which we have shown to have activated JNK [>>15<<], were highly resistant to 5-FU and GEM compared with their non-stem counterparts, essentially consistent with earlier reports [13, 14]." ; ns1:mentions . _:b36443793 rdf:type ns1:Context ; rdf:value "Here in this study, we first found that pancreatic CSCs, which we have shown to have activated JNK [15], were highly resistant to 5-FU and GEM compared with their non-stem counterparts, essentially consistent with earlier reports [>>13<<, 14]. We then demonstrated that inhibition of the activated JNK in pancreatic CSCs sensitized them to 5-FU and GEM and that JNK inhibition did so through elevation of the intracellular ROS level in combination with these chemotherapeutic" ; ns1:mentions . _:b36443794 rdf:type ns1:Context ; rdf:value "Here in this study, we first found that pancreatic CSCs, which we have shown to have activated JNK [15], were highly resistant to 5-FU and GEM compared with their non-stem counterparts, essentially consistent with earlier reports [13, >>14<<]. We then demonstrated that inhibition of the activated JNK in pancreatic CSCs sensitized them to 5-FU and GEM and that JNK inhibition did so through elevation of the intracellular ROS level in combination with these chemotherapeutic" ; ns1:mentions . _:b36443795 rdf:type ns1:Context ; rdf:value "Although JNK was originally identified as a positive regulator of cell death and overwhelming evidence does support the idea, JNK has also been shown to have a pro-survival function depending on the context [>>23<<\u201325]. Indeed, there are studies suggesting that the JNK pathway may play a positive role in chemoresistance of some cancer types [26]." ; ns1:mentions , , . _:b36443796 rdf:type ns1:Context ; rdf:value "Indeed, there are studies suggesting that the JNK pathway may play a positive role in chemoresistance of some cancer types [>>26<<]. However, the role of JNK in chemoresistance/sensitivity of pancreatic cancer cells, let alone pancreatic CSCs, to clinically relevant chemotherapeutic agents has remained largely unknown except for a report showing that GEM-induced" ; ns1:mentions . _:b36443797 rdf:type ns1:Context ; rdf:value "let alone pancreatic CSCs, to clinically relevant chemotherapeutic agents has remained largely unknown except for a report showing that GEM-induced apoptosis of pancreatic cancer cells was dependent on JNK-mediated DUSP1 expression [>>27<<]. In this regard, the present study is the very first to demonstrate that JNK has a protective role against 5-FU or GEM in pancreatic cancer cells, more specifically, in pancreatic CSCs." ; ns1:mentions . _:b36443798 rdf:type ns1:Context ; rdf:value "suggested that uPA and c-Met may also be involved in the chemoresistance of pancreatic CSCs, which is quite intriguing in light of the previous observations that JNK could function upstream and downstream of uPA and c-Met, respectively [>>28<<\u201330]. Although not pursued in the present study, investigation on the possible functional links among uPA, c-Met, and JNK may help better understand the whole picture of the molecular mechanism underlying the chemoresistance of pancreatic" ; ns1:mentions , , . _:b36443799 rdf:type ns1:Context ; rdf:value "It has been demonstrated that CSCs have lower intracellular ROS levels and that the low ROS levels are associated with the radioresistance of CSCs [>>31<<, 32]. In contrast to radioresistance, however, the role of enhanced ROS defense of CSCs in chemoresistance has yet to be established. Significantly, lines of evidence suggest that ROS may participate in the cytotoxic mechanisms of" ; ns1:mentions . _:b36443800 rdf:type ns1:Context ; rdf:value "It has been demonstrated that CSCs have lower intracellular ROS levels and that the low ROS levels are associated with the radioresistance of CSCs [31, >>32<<]. In contrast to radioresistance, however, the role of enhanced ROS defense of CSCs in chemoresistance has yet to be established. Significantly, lines of evidence suggest that ROS may participate in the cytotoxic mechanisms of" ; ns1:mentions . _:b36443801 rdf:type ns1:Context ; rdf:value "Significantly, lines of evidence suggest that ROS may participate in the cytotoxic mechanisms of chemotherapeutic agents such as 5-FU and GEM [>>17<<, 33\u201337], lending support to the idea that cellular antioxidant capacity may determine cells' sensitivity/resistance to such chemotherapeutic agents." ; ns1:mentions . _:b36443802 rdf:type ns1:Context ; rdf:value "Significantly, lines of evidence suggest that ROS may participate in the cytotoxic mechanisms of chemotherapeutic agents such as 5-FU and GEM [17, >>33<<\u201337], lending support to the idea that cellular antioxidant capacity may determine cells' sensitivity/resistance to such chemotherapeutic agents." ; ns1:mentions , , , , . _:b36443803 rdf:type ns1:Context ; rdf:value "In sharp contrast to the well-documented role of ROS in JNK activation [>>38<<, 39], the role of JNK in the control of the intracellular ROS level remains largely uninvestigated." ; ns1:mentions . _:b36443804 rdf:type ns1:Context ; rdf:value "In sharp contrast to the well-documented role of ROS in JNK activation [38, >>39<<], the role of JNK in the control of the intracellular ROS level remains largely uninvestigated." ; ns1:mentions . _:b36443805 rdf:type ns1:Context ; rdf:value "Interestingly, these two studies showed that activated JNK was localized to mitochondria and that JNK inhibition led to accumulation of mitochondrial superoxide [>>40<<, 41], pointing to the intriguing possibility that JNK may have a role in keeping the mitochondrial ROS level in check." ; ns1:mentions . _:b36443806 rdf:type ns1:Context ; rdf:value "Interestingly, these two studies showed that activated JNK was localized to mitochondria and that JNK inhibition led to accumulation of mitochondrial superoxide [40, >>41<<], pointing to the intriguing possibility that JNK may have a role in keeping the mitochondrial ROS level in check." ; ns1:mentions . _:b36443807 rdf:type ns1:Context ; rdf:value "Unlike in normal pancreas, JNK is activated in the majority of pancreatic cancers [>>42<<]. The significance of JNK activation in pancreatic cancer biology remained unclear, but we have only recently demonstrated that JNK activation by KRas, which is mutationally activated in the majority of pancreatic cancers, plays a key" ; ns1:mentions . _:b36443808 rdf:type ns1:Context ; rdf:value "we have only recently demonstrated that JNK activation by KRas, which is mutationally activated in the majority of pancreatic cancers, plays a key role in the maintenance of self-renewal and tumor-initiating capacity of pancreatic CSCs [>>15<<]. The findings of the present study now add a new role of JNK in pancreatic CSCs, namely, the maintenance of chemoresistance." ; ns1:mentions . _:b36443809 rdf:type ns1:Context ; rdf:value "The role of KRas in the chemoresistance of pancreatic CSCs still remains to be explored, but a previous study showed that Ras inhibition using farnesylthiosalicylic acid sensitized pancreatic cancer cells to GEM [>>43<<]. It might therefore be tempting to speculate that KRas contributes to the chemoresistance of pancreatic CSCs as well through the activation of the JNK-ROS defense axis." ; ns1:mentions . _:b36443810 rdf:type ns1:Context ; rdf:value "S, and M.O., unpublished observation), suggesting that \u201Crewiring\u201D of signaling pathways [>>44<<] may have taken place with some stability during the pre-treatment period, i.e., by the time cells were treated with 5-FU." ; ns1:mentions . _:b36443811 rdf:type ns1:Context ; rdf:value "On the other hand, GEM for instance reportedly exerts its cytotoxic effect on lung cancer cells through activation of JNK [>>45<<], suggesting the possibility that co-treatment could render the cells even more resistant to chemotherapeutic agents in case their cytotoxic effect is JNK-dependent." ; ns1:mentions . _:b567468985 rdf:type ns1:RelevantBibliographicResource . @prefix xsd: . _:b567468985 ns1:RelevantScore "8"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468986 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "6"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468987 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "6"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468988 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "5"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468989 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "5"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468990 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "5"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468991 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "4"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468992 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "4"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468993 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "4"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468994 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "4"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468995 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "4"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468996 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468997 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468998 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567468999 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469000 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469001 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469002 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469003 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469004 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469005 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469006 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469007 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469008 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469009 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469010 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469011 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469012 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469013 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469014 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "3"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469015 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469016 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469017 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469018 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469019 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469020 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469021 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469022 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469023 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469024 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469025 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469026 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469027 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469028 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469029 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469030 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469031 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469032 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469033 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469034 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469035 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469036 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469037 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469038 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469039 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469040 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469041 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469042 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469043 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469044 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469045 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469046 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469047 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469048 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469049 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469050 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469051 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469052 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469053 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469054 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469055 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469056 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469057 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469058 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469059 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469060 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469061 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469062 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469063 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469064 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469065 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469066 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469067 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469068 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469069 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469070 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469071 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469072 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469073 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469074 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469075 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469076 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469077 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469078 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469079 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469080 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469081 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469082 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469083 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469084 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469085 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469086 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469087 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469088 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469089 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469090 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469091 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469092 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469093 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469094 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469095 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469096 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469097 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469098 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469099 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469100 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469101 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469102 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469103 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469104 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469105 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469106 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469107 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469108 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId . _:b567469109 rdf:type ns1:RelevantBibliographicResource ; ns1:RelevantScore "2"^^xsd:nonNegativeInteger ; ns1:hasRelevantPaperId .