The DOI matches its Crossref record; 26 of the 27 references it cites were found in a registry or an index; none of the 14 sources its claims cite is checked for support yet.
The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate
Open accessAbstract
The somatic mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) observed in gliomas can lead to the production of 2-hydroxyglutarate (2HG). Here, we report that tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia (AML). Surprisingly, less than half of cases with elevated 2HG possessed IDH1 mutations. The remaining cases with elevated 2HG had mutations in IDH2, the mitochondrial homolog of IDH1. These data demonstrate that a shared feature of all cancer-associated IDH mutations is production of the oncometabolite 2HG. Furthermore, AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis.
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39 Own result · 18 Own interpretation · 13 Not checked yet · 8 Own method · 7 No basis given
In the paper
“There is a marked difference in the enzymatic rate of isocitrate-dependent NADPH production by the wild-type proteins and α-ketoglutarate-dependent NADPH consumption by both IDH1 and IDH2 mutants (Figure 2 and Dang et al., 2009).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
What the sources say
- Not checked yetcites Dang et al., 2009 source
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“None of the IDH2-mutated samples were found to also have somatic mutations in Flt-3, NPM1, or ASXL1”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
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In the paper
“IDH2 siRNA treated cells displayed a significant reduction in levels of citrate +5”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
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In the paper
“2HG production is a shared feature of heterozygous mutations in either cytosolic IDH1 or mitochondrial IDH2.”
- Also stated in: § 2HG as an onco-metabolite · plain
“All IDH mutations reported to date share the neomorphic ability to produce high levels of tumor 2HG.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“Here we report that the common feature of IDH1 and IDH2 mutations observed in AML and glioma is the acquisition of an enzymatic activity not shared by either wild-type enzyme.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
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- Also stated in: § 2HG as an onco-metabolite · plain
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In the paper
“we noted a trend towards improved survival in patients who presented with IDH2 mutations (p=0.08, Figure S2B)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
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“All samples displaying a signal ratio for 2HG/glutamate > 1% had either an IDH1 or IDH2 mutation”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
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In the paper
“extracts from cells expressing the R172K mutant IDH2 did not display isocitrate-dependent NADPH production above the levels observed in extracts from vector-transfected cells”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K enhances α-ketoglutarate-dependent NADPH consumption
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In the paper
“none of the samples with a 2HG/glutamate signal ratio ≤ 1% had an IDH mutation”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
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In the paper
“IDH2 R172K expressing cells were found to have an approximately 100-fold increase in the intracellular levels of 2HG compared with the levels detected in vector-transfected and IDH2 wild-type overexpressing cells”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K results in elevated 2HG levels
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In the paper
“despite the reduced ability to bind isocitrate, the R140Q mutant IDH2 is predicted to maintain its ability to bind and orient α-ketoglutarate in the active site”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
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In the paper
“AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > Abstract
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In the paper
“mutations in IDH1 did not appear to affect overall survival (p=0.37, Figure S2A)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
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In the paper
“we found an IDH2 R172K mutation in an AML sample obtained from a 77 year old female”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
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“known cytogenetic abnormalities were observed in 7/51 samples without IDH1/2 mutations (13.7%; all IDH mutants vs. IDH wild-type, p<0.05)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
plaincorrelationaln = 51 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Mutation of IDH2 R172K results in elevated 2HG levels”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K results in elevated 2HG levels
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In the paper
“The remaining cases with elevated 2HG had mutations in IDH2”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > Abstract
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In the paper
“less than half of cases with elevated 2HG possessed IDH1 mutations”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > Abstract
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In the paper
“tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > Abstract
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In the paper
“no change in citrate +4 levels was observed”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
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In the paper
“siRNA knockdown of either IDH1 or IDH2 can significantly reduce the proliferative capacity of a cancer cell line expressing both wild-type IDH1 and IDH2”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
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“All five of the IDH2 mutations producing 2HG in this sample set contained the same mutation, R140Q”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
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In the paper
“Nevertheless, both mutant proteins lead to an over 100-fold increase in tumor 2HG accumulation.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
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In the paper
“samples containing IDH2 R140Q mutations were found to have accumulated 2HG to levels 10–100 fold greater than the highest levels detected in IDH wild-type samples”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“control extracts have either had undetectable 2HG or a 2HG signal ≤ 1% of that for glutamate (n=13, p<0.001)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG
plainn = 13- Asserted: passes — The authors put it forward as true.
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In the paper
“IDH1 R132 and IDH2 R172 are analogous residues that both interact with the β-carboxyl of isocitrate”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH1 R132 and IDH2 R172 are analogous residues that both interact with the β-carboxyl of isocitrate
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In the paper
“Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG”
- Also stated in: § Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG · boosted
“every IDH1 R132H or IDH2 R172K mutant AML sample has exhibited evidence of 2HG accumulation”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG
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- Also stated in: § Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG · boosted
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In the paper
“Several cases with IDH2 R172 mutations were identified”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is mutated in AML
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“R172K mutant IDH2 expression was found to correlate with a significant enhancement to α-ketoglutarate-dependent NADPH consumption”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K enhances α-ketoglutarate-dependent NADPH consumption
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The 2HG levels in cancers with IDH mutations are consistently 10–100 fold elevated over levels found in samples lacking mutations of IDH1 or IDH2”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as a screening and diagnostic marker
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In the paper
“wild-type IDH2 overexpression also reproducibly enhanced α-ketoglutarate-dependent NADPH consumption under these conditions”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K enhances α-ketoglutarate-dependent NADPH consumption
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“every IDH1 R132H or IDH2 R172K mutant AML sample has exhibited evidence of 2HG accumulation, demonstrating a 2HG signal intensity by GC-MS analysis that is ≥ 30% of the intrasample glutamate signal”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Leukemic cells bearing heterozygous R172K IDH2 mutations accumulate 2HG
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the initial case, the IDH2 mutation found, R172K, was the same mutation reported in glioma samples”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is mutated in AML
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“IDH2 and IDH1 mutations were only observed in normal karyotype AML patients”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
plainn = 78- Asserted: passes — The authors put it forward as true.
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In the paper
“Mutant IDH2 produces the (R) enantiomer of 2HG”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutant IDH2 produces the (R) enantiomer of 2HG
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“extracts from cells expressing a comparable amount of wild-type IDH2 markedly increased isocitrate-dependent NADPH production”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > Mutation of IDH2 R172K enhances α-ketoglutarate-dependent NADPH consumption
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This is consistent with data presented here that IDH1-mutated and IDH2-mutated AML samples typically do not harbor other known mutations associated with AML, as well as a prior report that IDH-mutated gliomas often lack other mutations that are commonly acquired early in glioma pathogenesis (Yan et al., 2009).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Taken together, IDH mutations occur in 23% of samples analyzed here.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“Overall, IDH1 and IDH2 mutations were observed in over 23% of AML patients.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
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In the paper
“The product of this neomorphic enzyme activity can be readily detected in tumor samples and we show that tumor metabolite analysis can identify patients with tumor-associated IDH mutations.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Liquid chromatography-mass spectrometry (LC-MS)
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In the paper
“Although 2HG has been proposed to increase ROS levels in patients with inborn errors of 2HG metabolism (Kolker et al., 2002b; Latini et al., 2003), to date we have no evidence that the metabolite acts as a mutagen.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The product of this neomorphic enzyme activity can be readily detected in tumor samples and we show that tumor metabolite analysis can identify patients with tumor-associated IDH mutations.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Liquid chromatography-mass spectrometry (LC-MS)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using this method, we discovered a 2HG-producing IDH2 mutation, IDH2 R140Q, that was present in 9% of serial AML samples.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“IDH2 R140Q mutations occur in 9% of AML cases.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Liquid chromatography-mass spectrometry (LC-MS)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it is the truncated, non-carboxylating, reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate that is the common feature linking all cancer-associated IDH mutations”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Neomorphic enzymatic activity to produce 2HG is the shared feature of IDH1 and IDH2 mutations
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“provide a possible explanation for the lack of reduction to homozygosity for IDH2 mutations in cancer”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: All reported IDH1 or IDH2 mutations are heterozygous, with cancer cells retaining one wild-type copy of the relevant allele.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tumors displaying elevated 2HG are unlikely to be false positives”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as a screening and diagnostic marker
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Both IDH1 R132 and IDH2 R172 mutants lack the wild-type enzyme’s ability to convert isocitrate to α-ketoglutarate”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
- Not checked yetcites Yan et al., 2009 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This finding confirmed that both IDH1 and IDH2 mutations can occur in AML”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
boostedSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus in this sample set, 2HG measurement was predictive of IDH mutation status”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > 2HG can be used as a screening test for neomorphic IDH mutants
plaincorrelationaln = 18- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a shared feature of all cancer-associated IDH mutations is production of the onco-metabolite 2HG”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The roles of IDH1 and IDH2 in supporting cell proliferation are likely to be different.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, 2HG appears to be an important marker of IDH1/2-mutated neoplasms”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as a screening and diagnostic marker
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we have demonstrated that 2HG production is a common feature of the spontaneous mutations in these two IDH homologs”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Neomorphic enzymatic activity to produce 2HG is the shared feature of IDH1 and IDH2 mutations
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data argue against the IDH mutations resulting in a simple loss of function”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: All reported IDH1 or IDH2 mutations are heterozygous, with cancer cells retaining one wild-type copy of the relevant allele.
- Rests on an assumption: No patient has been reported with both an IDH1 and IDH2 mutation.
In the paper
“2HG was found to be elevated in IDH1-mutated gliomas”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
- Not checked yetcites Dang et al., 2009 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This is consistent with data presented here that IDH1-mutated and IDH2-mutated AML samples typically do not harbor other known mutations associated with AML, as well as a prior report that IDH-mutated gliomas often lack other mutations that are commonly acquired early in glioma pathogenesis (Yan et al., 2009).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
What the sources say
- Not checked yetcites Yan et al., 2009 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For now, it appears to represent a highly correlative maker for an emerging class of somatic mutations in the isocitrate dehydrogenase enzymes.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The identification of frequent IDH2 mutations in AML increases the significance of this family of mutations in understanding the pathogenesis of AML.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In an AML case with an IDH1 mutation that was sequenced in its entirety (Mardis et al., 2009), there were a relatively small total number of somatic, non-synonymous mutations.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
What the sources say
- Not checked yetcites Mardis et al., 2009 source
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In the case of IDH1 mutant proteins, it has been reported that a local supply of NADPH and α-ketoglutarate is required to drive 2HG production (Dang et al., 2009).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
What the sources say
- Not checked yetcites Dang et al., 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, these mutations appear to define a significant subset of CNS tumors and leukemias.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as an onco-metabolite
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: IDH mutations occur frequently in gliomas with mixed astrocytic and oligodendroglial features and in acute myeloid leukemias.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, for the neomorphic activity of mitochondrial IDH2 mutants, the requirement for local generation of substrate is unlikely to be absolute.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Mitochondrial α-ketoglutarate levels are kept high by various anaplerotic substrates.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the context of a wild-type/mutant IDH1 heterodimer, the required substrates for the mutant’s neomorphic activity are most readily provided by the wild-type subunit’s normal activity on NADP+ and isocitrate.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: IDH1 contributes to cytosolic NADPH production.
- It may state two separate claims as one. 10
- Probably not a substantial claim. 17
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In addition, it appears that both wild-type IDH1 and IDH2 can play positive and non-redundant roles in cell proliferation.”
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
“Both wild-type IDH1 and IDH2 are required for cell proliferation.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Liquid chromatography-mass spectrometry (LC-MS) · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While IDH1 mutations were found in 7.7% of samples in this analysis (6/78), twice as many mutations were detected in IDH2, at a frequency of 15.4% (12/78, p<0.05)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
plainn = 78 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“IDH2 mutations are more common than IDH1 mutations in AML”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 mutations are more common than IDH1 mutations in AML
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“when cells were treated with one of two independent siRNAs against IDH3, there was a reproducible increase in citrate +5, while citrate +4 was unchanged”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Overall, IDH2 mutations appear more common than IDH1 mutations in AML.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Liquid chromatography-mass spectrometry (LC-MS)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Mutations in human cytosolic isocitrate dehydrogenase I (IDH1) occur somatically in >70% of grade II-III gliomas and secondary glioblastomas, and in 8.5% of acute myeloid leukemias (AML)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These IDH1 R132 mutations were observed in 8.5% of AML patients studied, and a significantly higher percentage of mutation was observed in the subset of patients whose tumors lacked cytogenetic abnormalities”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
- Not checked yetcites Mardis et al., 2009 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“cancer-associated IDH1 R132 mutants display a loss-of-function for the use of isocitrate as substrate, with a concomitant gain-of-function for the reduction of α-ketoglutarate to 2HG”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is mutated in AML
What the sources say
- Not checked yetcites Dang et al., 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data support a role for IDH2 and not IDH3 in the conversion of α-ketoglutarate into citrate by reductive carboxylation in the mitochondria”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > RESULTS > IDH2 is critical for proliferating cells and contributes to the conversion of α-ketoglutarate into citrate in the mitochondria
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The R132H IDH1 mutation observed in gliomas was found to display a gain of function for the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG)”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > INTRODUCTION
What the sources say
- Not checked yetcites Dang et al., 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After redissolving samples in deionized water, citrate was detected on two different LC-MS approaches, both of which gave comparable results.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Liquid chromatography-mass spectrometry (LC-MS)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Human IDH2 has 97% homology with pig IDH2, and none of the 13 residues that are different (out of 418 total, excluding the N-terminal mitochondrial signal sequence) are found in the active site.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Structural modeling
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While the exact role of wild-type IDH2 in supporting cell growth will require further investigation, this requirement correlates with the ability of IDH2 to contribute to the conversion of α-ketoglutarate into citrate via a pathway of reductive carboxylation in the mitochondria of proliferating cells.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For all experiments, OD340 changes in assay buffer lacking lysate protein were measured and subsequently subtracted from the OD340 changes measured in lysate replicates to arrive at final values.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Cell lysate based enzyme assays
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Actin antibody (Santa Cruz, sc1616) was also used to assess equal protein loading of Western blots.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Western blot
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Isotopomer distributions were simultaneously corrected for naturally occurring heavy isotopes of all elements in each mass fragment using a correction matrix as previously described (Weckwerth, 2007).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Gas chromatography-mass spectrometry (GC-MS) analysis
What the sources say
- Not checked yetcites Weckwerth, 2007
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Identification of the 2HG metabolite peak was confirmed using standards obtained from Sigma.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Gas chromatography-mass spectrometry (GC-MS) analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A PDB structure of pig IDH2 is available, with isocitrate in the active site (1LWD) (Ceccarelli et al., 2002).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Structural modeling
What the sources say
- Not checked yetcites Ceccarelli et al., 2002 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“for samples with less than 70% blasts flow cytometric sorting (FACSAria) was used to isolate blast cells according to leukemic blast immunophenotype before DNA isolation.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Sequence Analysis of IDH1 and IDH2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Wild-type and mutant sequences were then subcloned into pcDNA3 (Invitrogen) and confirmed by direct sequencing before expression in mammalian cells.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Constructing IDH1 and IDH2 mutants
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All DNA samples were whole genome amplified using Ø29 polymerase and mutations were validated on unamplified DNA to ensure all mutations were present in the diagnostic sample.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Sequence Analysis of IDH1 and IDH2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sequence analysis was performed using Mutation Surveyor (SoftGenetics, State College PA) and all mutations were validated by repeat PCR and sequencing on unamplified DNA from the archival sample.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > EXPERIMENTAL PROCEDURES > Sequence Analysis of IDH1 and IDH2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Mitochondria typically have a high NADPH/NADP+ ratio, supported in part by the ability to interconvert NADPH and NADH in the matrix (Rydstrom, 2006).”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
What the sources say
- Not checked yetcites Rydstrom, 2006 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
All reported IDH1 or IDH2 mutations are heterozygous, with cancer cells retaining one wild-type copy of the relevant allele.
“To date, all reported IDH1 or IDH2 mutations are heterozygous, with the cancer cells retaining one wild-type copy of the relevant IDH1 or IDH2 allele”
The paper relies on this without support.
No patient has been reported with both an IDH1 and IDH2 mutation.
“No patient has been reported with both an IDH1 and IDH2 mutation”
The paper relies on this without support.
All reported IDH1 mutations result in an amino acid substitution at a single arginine residue in the enzyme's active site, R132.
“To date, all reported IDH1 mutations result in an amino acid substitution at a single arginine residue in the enzyme’s active site, R132”
The paper relies on this without support.
IDH2 mutations identified in gliomas occur at the analogous residue to IDH1 R132, IDH2 R172.
“The IDH2 mutations which have been identified in gliomas occur at the analogous residue to IDH1 R132, IDH2 R172”
The paper relies on this without support.
IDH1 contributes to cytosolic NADPH production.
“IDH1 contributes to cytosolic NADPH production.”
The paper relies on this without support.
Mitochondrial α-ketoglutarate levels are kept high by various anaplerotic substrates.
“In addition, mitochondrial α-ketoglutarate is maintained at high levels by a variety of anaplerotic substrates.”
The paper relies on this without support.
IDH mutations occur frequently in gliomas with mixed astrocytic and oligodendroglial features and in acute myeloid leukemias.
“a possibility by which 2HG might contribute to tumorigenesis emerges from consideration of the tumor subtypes in which IDH mutations are found with high frequency: gliomas with mixed astrocytic and oligodendroglial features, and acute myeloid leukemias.”
The paper relies on this without support.
In those two tumor types, disease centers on proliferation of relatively undifferentiated cells, and pathogenesis involves a differentiation block rather than only faster proliferation.
“In both cases, proliferation of a relatively undifferentiated cell population is central to the disease, and pathogenesis is marked by a block to differentiation rather than simply by an increase in proliferative rate.”
The paper relies on this without support.
Most enzyme mutations linked to cancer cause either loss of catalysis or constitutive activation.
“Most cancer-associated enzyme mutations result in either catalytic inactivation or constitutive activation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, 2-HG acts as a competitive inhibitor of α-KG, and its production by mutant IDH1 consumes α-KG (81, 99), leading to reduced TET2 and JmjC activity in tumor cells (79, 80).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [99]
Experimental — accuracy not yet measuredIn the citing paper
“Wild-type IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate (αKG) and CO2 (Figure 4a). Cancer associated mutations in IDH1 and IDH2 eliminate this function and confer a neomorphic activity to the enzyme, generating D-2-hydroxyglutarate (D-2HG) via the reduction of αKG (Figure 4b)(Dang et al., 2009; Ward et al., 2010).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ward et al., 2010
In the citing paper
“Thus, various tumors, including glioma, secondary glioblastoma, and acute myeloid leukemia (AML), harboring heterozygous point mutations in the active sites of IDH1/2 show dramatic increases in the R-2-HG levels111,113–115.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [113]
In the citing paper
“The high concentrations of R-2HG (more than 10 mM) that have been observed in malignant brain tumours and leukaemias (Dang et al, 2009;Gross et al, 2010;Ward et al, 2010), might be sufficient to inhibit even the less-susceptible 2OG oxygenases.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Ward et al, 2010
In the citing paper
“As production of 2HG by IDH mutations is stereospecific (Dang et al, 2009;Ward et al, 2010), the specificity of inhibition by the 2HG enantiomers is relevant to their potential as mediators of oncogenic pathways.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Ward et al, 2010
In the citing paper
“However, they also cause a gain of function comprising catalysis of 2OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG; Dang et al, 2009;Gross et al, 2010;Ward et al, 2010).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Ward et al, 2010
In the citing paper
“Tumor-associated IDH mutations unmask a latent ability of these enzymes to produce the R enantiomer of 2-hydroxyglutarate, which accumulates to low millimolar levels in IDH mutant tumors (Dang et al., 2009; Gross et al., 2010; Ward et al., 2010).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Ward et al., 2010
In the citing paper
“Oncogenic mutations in genes encoding IDH1/2 result in neomorphic enzyme activity that favors reduction of αKG to d-2-hydroxyglutarate (D-2HG) (167, 168).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [168]
In the citing paper
“In contrast to wild-type isocitrate dehydrogenases, which convert the TCA cycle metabolite isocitrate to α-ketoglutarate, a mutant form of IDH prefers to use α-ketoglutarate as a substrate, catalyzing its conversion to the D-enantiomer of 2-hydroxyglutarate (2-HG) (Dang et al., 2010; Ward et al., 2010).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Ward et al., 2010
In the citing paper
“the common feature of this remaining subset of 2HG-elevated AMLs was another mutation in IDH2, occurring at R140 (Ward et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward et al., 2010
In the citing paper
“Enzymatic assays and measurement of 2HG levels in primary AML samples confirmed that these IDH2 R172 mutations result in 2HG elevation (Gross et al., 2010; Ward et al., 2010).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward et al., 2010
In the citing paper
“some 2HG-elevated AML samples lacked IDH1 R132 or IDH2 R172 mutations”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward et al., 2010
In the citing paper
“has been investigated since then as a way to produce citrate and fatty acids from α-ketoglutarate derived from glutamine (Holleran et al., 1995; Ward et al., 2010; Yoo et al., 2008)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward et al., 2010
In the citing paper
“R(-)-2HG (also known as D-2HG) is the exclusive 2HG stereoisomer produced by IDH1 and IDH2 mutants (Dang et al., 2009; Ward et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Ward et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > Maintaining at least one IDH1 and IDH2 wild-type allele may be essential for transformed cells
“Nevertheless, both mutant proteins lead to an over 100-fold increase in tumor 2HG accumulation.”
§ The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate > DISCUSSION > 2HG as a screening and diagnostic marker
“The 2HG levels in cancers with IDH mutations are consistently 10–100 fold elevated over levels found in samples lacking mutations of IDH1 or IDH2.”
Citations
Cites
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147
IDH1 and IDH2 Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Self-citationThe Consensus Coding Sequences of Human Breast and Colorectal Cancers
Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D. L., Leary, R. J., Ptak, J., Silliman, N., et al. (2006) · Science · doi:10.1126/science.1133427 · Cited by 3,161 · cited 1×
“Mutations have also been reported in cancers of the colon and prostate (Kang et al., 2009; Sjoblom et al., 2006).”
BackgroundDeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622 · cited 1×
“IDH1 is one of only three cytosolic enzymes that contribute to the NADPH production required for nucleotide and lipid biosynthesis during cell growth (DeBerardinis et al., 2007).”
BackgroundSelf-citationRecurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219
Hartmann, C. J., Meyer, J., Balß, J., Capper, D., Mueller, W. C., Christians, A., Felsberg, J., Wolter, M., Mawrin, C., Wick, W., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0561-9 · Cited by 1,163 · cited 1×
“This is in contrast to the data reported for gliomas in which less than 5% of IDH mutations were in IDH2 (Hartmann et al., 2009; Yan et al., 2009).”
ResultGlioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119 · cited 1×
“Therefore, it has been proposed that mutant IDH1 can act as a dominant negative against wild-type IDH1 function, resulting in a decrease in cytosolic a-ketoglutarate levels and leading to an indirect activation of the HIF-1a pathway (Zhao et al., 2009).”
BackgroundBajad, S. U., Lu, W., Kimball, E., Yuan, J., Peterson, C. N., & Rabinowitz, J. D. (2006) · Journal of Chromatography A · doi:10.1016/j.chroma.2006.05.019 · Cited by 593 · cited 1×
“Reactions used to monitor other TCA components have been described previously (Bajad et al., 2006).”
MethodSelf-citationAnalytical strategies for LC–MS-based targeted metabolomics
Lu, W., Bennett, B. D., & Rabinowitz, J. D. (2008) · Journal of Chromatography B · doi:10.1016/j.jchromb.2008.04.031 · Cited by 489 · cited 1×
“In both cases, LC separation was by reversed phase chromatography using tributylamine as an ion pairing agent (Lu et al., 2008; Luo et al., 2007) with ionization by negative electrospray at 23 kV.”
MethodSelf-citation
Cited by
Sorted by citations
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926
Self-citationRegulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744
“Subsequent studies revealed that IDH1 or IDH2 is mutated in approximately 80% of adult grade II and grade III gliomas and secondary glioblastomas, and in approximately 30% of cytogenetically normal cases of AM”
BackgroundMetabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
“Likewise, following the discovery of 2HG-producing IDH2 R140 mutations in leukemia, researchers looked for and successfully found germline IDH2 R140 mutations in D-2HG aciduria.”
BackgroundMethodInfluentialSelf-citationAerobic glycolysis: Meeting the metabolic requirements of cell proliferation
Lunt, S. Y., & Vander Heiden, M. G. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154237 · Cited by 3,057
“Additional work is required to determine which cancer cells rely on NADPH production via IDH1, malic enzyme, and/or the oxidative pentose phosphate pathway.”
Influential
Metadata
- Authors
- Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., Rabinowitz, J. D., Carroll, M., Su, S. M., Sharp, K. A., Levine, R. L., & Thompson, C. B.
- Affiliations
- Abramson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Princeton University (US)
- Agios Pharmaceuticals (United States) (US)
- University of Pennsylvania (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 17
- Issue
- 3
- Pages
- 225-234
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2849316
- OpenAlex
- W1995675594
- Cited by
- 2,020
- References
- 27
- Citations by year
- 2026: 76 · 2025: 68 · 2024: 113 · 2023: 102 · 2022: 111 · 2021: 149 · 2020: 137 · 2019: 148 · 2018: 133 · 2017: 127 · 2016: 151 · 2015: 140 · 2014: 110 · 2013: 126 · 2012: 126
- FWCI
- 90.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- Memorial Sloan-Kettering Cancer Center
- Agios Pharmaceuticals
- National Cancer Institute (P01CA104838, R01CA092660, R01CA105463)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, IDH2 mutation, 2-hydroxyglutarate, acute myeloid leukemia, oncometabolites, alpha-ketoglutarate, isocitrate dehydrogenase, chromosomal abnormalities, glioma
- MeSH terms
- Glutarates, Humans, Isocitrate Dehydrogenase, Isocitrates, Ketoglutaric Acids, Mitochondria, Mutation, Tumor Cells, Cultured, Leukemia, Myeloid, Acute, Cell Proliferation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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