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Statements

Subject Item: n2:23555045
rdf:type: n4:CitationPaper n4:RelevantPaper n4:ReferencePaper
rdfs:seeAlso: n8:10.1371%2Fjournal.pone.0059594 n9:23555045 n10:0 n11:0
bibo:cites: n2:17200426 n2:10835681 n2:9440739 n2:10848777 n2:10430060 n2:8552605 n2:20551514 n2:16825499 n2:16732270 n2:3298524 n2:11752096 n2:16582916 n2:21067383 n2:14617757 n2:18587011 n2:10807772 n2:9305600 n2:1967217 n2:17090675 n2:14564000 n2:19179314 n2:18227842 n2:21319998 n2:19892975 n2:197411 n2:1352414 n2:11961146 n2:9458240 n2:11877259
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n4:hasRelevantBibliographicResourceOf: _:vb519154383
n4:pmcid: PMC0
bibo:doi: 10.1371%2Fjournal.pone.0059594
n5:contains: _:vb21722988 _:vb21722991 _:vb21722994 _:vb21722958

Subject Item: _:vb21722958
rdf:type: n5:Section
dc:title: introduction
n5:contains: _:vb21722972 _:vb21722973 _:vb21722974 _:vb21722975 _:vb21722968 _:vb21722969 _:vb21722970 _:vb21722971 _:vb21722964 _:vb21722965 _:vb21722966 _:vb21722967 _:vb21722960 _:vb21722961 _:vb21722962 _:vb21722963 _:vb21722959 _:vb21722984 _:vb21722985 _:vb21722986 _:vb21722987 _:vb21722980 _:vb21722981 _:vb21722982 _:vb21722983 _:vb21722976 _:vb21722977 _:vb21722978 _:vb21722979

Subject Item: _:vb21722959
rdf:type: n4:Context
rdf:value: In the past decade, several clinical trials have been carried out that have highlighted both the promise of gene therapy [>>1<<], [2], [3], [4] and the potential harm from the uncontrolled integrations of the viral vectors used to deliver the therapeutic transgene [5], [6].
n4:mentions: n2:19179314

Subject Item: _:vb21722960
rdf:type: n4:Context
rdf:value: In the past decade, several clinical trials have been carried out that have highlighted both the promise of gene therapy [1], [>>2<<], [3], [4] and the potential harm from the uncontrolled integrations of the viral vectors used to deliver the therapeutic transgene [5], [6].
n4:mentions: n2:21067383

Subject Item: _:vb21722961
rdf:type: n4:Context
rdf:value: In the past decade, several clinical trials have been carried out that have highlighted both the promise of gene therapy [1], [2], [>>3<<], [4] and the potential harm from the uncontrolled integrations of the viral vectors used to deliver the therapeutic transgene [5], [6].
n4:mentions: n2:19892975

Subject Item: _:vb21722962
rdf:type: n4:Context
rdf:value: In the past decade, several clinical trials have been carried out that have highlighted both the promise of gene therapy [1], [2], [3], [>>4<<] and the potential harm from the uncontrolled integrations of the viral vectors used to deliver the therapeutic transgene [5], [6].
n4:mentions: n2:11961146

Subject Item: _:vb21722963
rdf:type: n4:Context
rdf:value: clinical trials have been carried out that have highlighted both the promise of gene therapy [1], [2], [3], [4] and the potential harm from the uncontrolled integrations of the viral vectors used to deliver the therapeutic transgene [>>5<<], [6]. In contrast to gamma-retroviral vectors, which integrate preferentially near transcriptional start sites, lentiviral vectors (LVs) show safer integration profiles and are considered less genotoxic than gamma-retroviral vectors [7],
n4:mentions: n2:16582916

Subject Item: _:vb21722964
rdf:type: n4:Context
rdf:value: trials have been carried out that have highlighted both the promise of gene therapy [1], [2], [3], [4] and the potential harm from the uncontrolled integrations of the viral vectors used to deliver the therapeutic transgene [5], [>>6<<]. In contrast to gamma-retroviral vectors, which integrate preferentially near transcriptional start sites, lentiviral vectors (LVs) show safer integration profiles and are considered less genotoxic than gamma-retroviral vectors [7], [8].
n4:mentions: n2:14564000

Subject Item: _:vb21722965
rdf:type: n4:Context
rdf:value: In contrast to gamma-retroviral vectors, which integrate preferentially near transcriptional start sites, lentiviral vectors (LVs) show safer integration profiles and are considered less genotoxic than gamma-retroviral vectors [>>7<<], [8]. Lentiviral vectors have been used in clinical trials, however these studies used myeloablative conditioning and/or relatively high multiplicities of infection (MOIs) for transduction in order to achieve sufficient numbers of
n4:mentions: n2:16825499

Subject Item: _:vb21722966
rdf:type: n4:Context
rdf:value: In contrast to gamma-retroviral vectors, which integrate preferentially near transcriptional start sites, lentiviral vectors (LVs) show safer integration profiles and are considered less genotoxic than gamma-retroviral vectors [7], [>>8<<]. Lentiviral vectors have been used in clinical trials, however these studies used myeloablative conditioning and/or relatively high multiplicities of infection (MOIs) for transduction in order to achieve sufficient numbers of transduced
n4:mentions: n2:16732270

Subject Item: _:vb21722967
rdf:type: n4:Context
rdf:value: vectors have been used in clinical trials, however these studies used myeloablative conditioning and/or relatively high multiplicities of infection (MOIs) for transduction in order to achieve sufficient numbers of transduced cells [>>3<<], [9], which may increase the risk for insertional mutagenesis.
n4:mentions: n2:19892975

Subject Item: _:vb21722968
rdf:type: n4:Context
rdf:value: vectors have been used in clinical trials, however these studies used myeloablative conditioning and/or relatively high multiplicities of infection (MOIs) for transduction in order to achieve sufficient numbers of transduced cells [3], [>>9<<], which may increase the risk for insertional mutagenesis.
n4:mentions: n2:17090675

Subject Item: _:vb21722969
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [>>10<<], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:10835681

Subject Item: _:vb21722970
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [>>11<<], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:9440739

Subject Item: _:vb21722971
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [>>12<<], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:9458240

Subject Item: _:vb21722972
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [>>13<<], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:1352414

Subject Item: _:vb21722973
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [>>14<<], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:3298524

Subject Item: _:vb21722974
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [>>15<<], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:11752096

Subject Item: _:vb21722975
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [>>16<<], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:1967217

Subject Item: _:vb21722976
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [>>17<<] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [22] have been tested extensively in this context.
n4:mentions: n2:10430060

Subject Item: _:vb21722977
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [>>18<<], [19], [20], [21], [22] have been tested extensively in this context. It has been shown that the use of all 3 systems results in an enrichment of gene-corrected blood cells in mice.
n4:mentions: n2:8552605

Subject Item: _:vb21722978
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [>>19<<], [20], [21], [22] have been tested extensively in this context. It has been shown that the use of all 3 systems results in an enrichment of gene-corrected blood cells in mice.
n4:mentions: n2:20551514

Subject Item: _:vb21722979
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [>>20<<], [21], [22] have been tested extensively in this context. It has been shown that the use of all 3 systems results in an enrichment of gene-corrected blood cells in mice.
n4:mentions: n2:21319998

Subject Item: _:vb21722980
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [>>21<<], [22] have been tested extensively in this context. It has been shown that the use of all 3 systems results in an enrichment of gene-corrected blood cells in mice.
n4:mentions: n2:10807772

Subject Item: _:vb21722981
rdf:type: n4:Context
rdf:value: To this end, the multidrug resistance gene (MDR-1) [10], [11], [12], [13], the dihydrofolate-reductase gene (DHFR) [14], [15], [16], [17] and the O6-methylguanine-DNA-methyltransferase gene (MGMT) [18], [19], [20], [21], [>>22<<] have been tested extensively in this context. It has been shown that the use of all 3 systems results in an enrichment of gene-corrected blood cells in mice.
n4:mentions: n2:14617757

Subject Item: _:vb21722982
rdf:type: n4:Context
rdf:value: Selection at the stem cell level could unambiguously be demonstrated only with the MGMT system, resulting in efficient and stable MGMTP140K-mediated multi-lineage selection in both macaque and baboon nonhuman primate models [>>19<<], and the first report of its clinical testing was recently reported [23].
n4:mentions: n2:20551514

Subject Item: _:vb21722983
rdf:type: n4:Context
rdf:value: Furthermore, the carcinogenic potential of alkylating drugs represents a considerable risk for clinical applications of this approach [24], [>>25<<].
n4:mentions: n2:11877259

Subject Item: _:vb21722984
rdf:type: n4:Context
rdf:value: an alternative approach to HPC selection that relies on shRNA mediated knockdown of hypoxanthine phosphoribosyl transferase (HPRT), the enzyme required for metabolizing purine analogs like 6-thioguanine (6TG) into active agents [>>26<<]. This approach has several advantages. First, the sequence needed to induce drug resistance is very short (48 bases), making subsequent inclusion of a therapeutic gene and regulatory elements simpler and more efficient.
n4:mentions: n2:18587011

Subject Item: _:vb21722985
rdf:type: n4:Context
rdf:value: And although anti-metabolites may contribute to leukemogenesis [>>27<<], in the absence of concomitant administration of highly genotoxic medications, this risk is quite low [27], [28].
n4:mentions: n2:10848777

Subject Item: _:vb21722986
rdf:type: n4:Context
rdf:value: And although anti-metabolites may contribute to leukemogenesis [27], in the absence of concomitant administration of highly genotoxic medications, this risk is quite low [>>27<<], [28]. Third, this strategy provides drug resistance without the introduction of a mutated protein that might lead to immunologic elimination of transduced cells. More recently, another group showed that 6TG can be used for conditioning
n4:mentions: n2:10848777

Subject Item: _:vb21722987
rdf:type: n4:Context
rdf:value: And although anti-metabolites may contribute to leukemogenesis [27], in the absence of concomitant administration of highly genotoxic medications, this risk is quite low [27], [>>28<<]. Third, this strategy provides drug resistance without the introduction of a mutated protein that might lead to immunologic elimination of transduced cells. More recently, another group showed that 6TG can be used for conditioning as well
n4:mentions: n2:17200426

Subject Item: _:vb21722988
rdf:type: n5:Section
dc:title: materials and methods
n5:contains: _:vb21722989 _:vb21722990

Subject Item: _:vb21722989
rdf:type: n4:Context
rdf:value: Molm13 and REH cell lines [>>31<<], [32], generous gifts from the laboratory of James DeGregori, were maintained in RPMI media supplemented with 10% FBS.
n4:mentions: n2:197411

Subject Item: _:vb21722990
rdf:type: n4:Context
rdf:value: Molm13 and REH cell lines [31], [>>32<<], generous gifts from the laboratory of James DeGregori, were maintained in RPMI media supplemented with 10% FBS.
n4:mentions: n2:9305600

Subject Item: _:vb21722991
rdf:type: n5:Section
dc:title: results
n5:contains: _:vb21722992 _:vb21722993

Subject Item: _:vb21722992
rdf:type: n4:Context
rdf:value: Importantly, both sh0G and sh491G transduced cells stopped proliferating in the presence of cisplatinum, indicating that MMR remained intact and that the effects observed were specific to 6TG (Supplemental Figure 3d ) [>>26<<]. These data indicate that human hematopoietic progenitor cells can be provided with specific resistance to 6TG with lentiviral delivered knockdown of HPRT.
n4:mentions: n2:18587011

Subject Item: _:vb21722993
rdf:type: n4:Context
rdf:value: As we have never observed 6TG resistance in non-silencing control transduced mouse [>>26<<] or human cells, the non-silencing control vector was omitted from subsequent experiments to reduce the numbers of experimental mice.
n4:mentions: n2:18587011

Subject Item: _:vb21722994
rdf:type: n5:Section
dc:title: discussion
n5:contains: _:vb21722996 _:vb21722997 _:vb21722998 _:vb21722999 _:vb21722995

Subject Item: _:vb21722995
rdf:type: n4:Context
rdf:value: These results extend our previous report in which we showed efficient in vivo selection of murine HSCs transduced with LVs expressing HPRT shRNAs [>>26<<]. Recent studies by Hacke et al [29] used 6TG as a single agent for pre-transplant conditioning as well as in vivo selection of HPRT deficient mouse BM, corroborating the effectiveness of this strategy.
n4:mentions: n2:18587011

Subject Item: _:vb21722996
rdf:type: n4:Context
rdf:value: Adverse events directly related to retroviral-mediated insertional mutagenesis in human trials, have been reported in some patients enrolled in gene-therapy clinical trials [>>5<<], [6], [30]. These effects are in part, mediated by the high MOIs used to achieve high transduction efficiencies.
n4:mentions: n2:16582916

Subject Item: _:vb21722997
rdf:type: n4:Context
rdf:value: Adverse events directly related to retroviral-mediated insertional mutagenesis in human trials, have been reported in some patients enrolled in gene-therapy clinical trials [5], [>>6<<], [30]. These effects are in part, mediated by the high MOIs used to achieve high transduction efficiencies.
n4:mentions: n2:14564000

Subject Item: _:vb21722998
rdf:type: n4:Context
rdf:value: Adverse events directly related to retroviral-mediated insertional mutagenesis in human trials, have been reported in some patients enrolled in gene-therapy clinical trials [5], [6], [>>30<<]. These effects are in part, mediated by the high MOIs used to achieve high transduction efficiencies.
n4:mentions: n2:18227842

Subject Item: _:vb21722999
rdf:type: n4:Context
rdf:value: While we were able to achieve increases of up to 80% of transduced human cells, the extent and consistency of selection that we observed was less than that of other reports with ΔMGMT [>>22<<]. Differences in experimental design, including the timepoints at which engraftment and selection efficiency were examined, may contribute to these differences.
n4:mentions: n2:14617757

Subject Item: _:vb519154383
rdf:type: n4:RelevantBibliographicResource
n4:RelevantScore: 2
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