The DOI matches its Crossref record; 144 of the 145 references it cites were found in a registry or an index; none of the 80 sources its claims cite is checked for support yet.
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Open accessAbstract
Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria, but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer.
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TL;DR
This review argues that metabolic reprogramming is a core hallmark of cancer, driven by oncogenes and tumor suppressors to support anabolic growth rather than arising passively from mitochondrial damage. It highlights mitochondrial biosynthetic roles, PKM2 and other metabolic enzyme alterations, and oncometabolites such as 2HG that can disrupt epigenetics and differentiation.
Key findings
- Altered metabolism is not merely a secondary response to proliferation signals; it results from active reprogramming by oncogenes and tumor suppressors and is selected during tumorigenesis. Most tumor mitochondria are not defective in oxidative phosphorylation, contrary to Warburg’s original hypothesis.
- PI3K/Akt/mTORC1 and Myc reprogram mitochondrial metabolism for biosynthesis: Akt activates ACL to divert mitochondrial citrate to acetyl-CoA, mTORC1 promotes mitochondrial biogenesis and SREBP-mediated lipogenesis, and Myc enhances glutaminase expression and glutamine addiction. HIF-1 can inhibit PDH via PDK1, blocking glucose carbon entry into mitochondrial citrate and correlating with anti-proliferative effects in some contexts.
- PKM2 is the predominant pyruvate kinase isoform in embryonic tissues and all cancer cells examined to date; it has intrinsically lower enzymatic activity than PKM1 and is sensitive to tyrosine kinase inhibition, proposed to facilitate shunting of glycolytic intermediates into anabolic pathways. At least 11 proteins have been reported to bind PKM2.
- IDH1/IDH2 mutations produce the oncometabolite 2HG, which inhibits α-ketoglutarate-dependent dioxygenases including TET enzymes and histone demethylases, altering DNA and histone methylation and impairing differentiation. IDH2 R140 mutations now account for nearly half of all cases of D-2HG aciduria; succinate and fumarate are also described as oncometabolites.
Methods
- Design: Review article; no primary experimental design is reported.
- Data or sample: Not stated in the paper as a primary dataset; the text synthesizes cited studies across cancer metabolism, oncogene/tumor suppressor signaling, metabolic enzyme isoforms, and oncometabolite biology.
- Main analysis: Conceptual and literature-based synthesis arguing that metabolic reprogramming should be considered a core cancer hallmark.
Limitations
- The paper states that current methods cannot reliably distinguish cytosolic metabolites from mitochondrial and other compartmentalized pools; fractionation methods often cause metabolite leakage, and distinct metabolite pools may exist due to enzyme channeling.
- The paper states that quantitative measurement of metabolic flux remains challenging, including obstacles such as cellular compartmentalization and reliance on complex, incompletely defined cell culture media.
- The paper states that non-cell autonomous effects of tumor metabolism are an emerging challenge, including lactate acidification, possible symbiosis between lactate-producing and lactate-consuming cells, and fatty acid exchange between omental adipocytes and ovarian carcinoma cells. The text also makes evident that unresolved issues remain, such as conflicting conclusions over whether reductive glutamine flux depends primarily on cytosolic IDH1 or mitochondrial IDH2, the role of 2HG in PHD2/HIF regulation, and which alternative NADPH-generating pathways are most important.
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Claims the paper makes
63 Not checked yet · 39 Own interpretation · 13 No basis given
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In the paper
“Evidence is also developing for the proposal that proto-oncogenes and tumor suppressors primarily evolved to regulate metabolism.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Introduction
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In the paper
“We contend that altered metabolism has attained the status of a core hallmark of cancer.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Abstract
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In the paper
“Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria, but result from oncogene-directed metabolic reprogramming required to support anabolic growth.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Abstract
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“Activated PI3K/Akt leads to enhanced glucose uptake and glycolysis (Buzzai et al., 2005; Elstrom et al., 2004).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > PI3K/Akt/mTORC1 activation: driving anabolic metabolism and tumorigenesis by reprogramming mitochondria
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“In fact, most cancer cells and proliferating normal cells still derive a significant fraction of their ATP through oxidative phosphorylation.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Altered metabolism is a direct response to growth factor signaling
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In the paper
“Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Abstract
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In the paper
“Rather than ATP, proliferating cells are in much greater need of reduced carbon and reduced nitrogen, as well as cytosolic NADPH for reductive biosynthetic reactions.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Altered metabolism is a direct response to growth factor signaling
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In the paper
“However, in contrast to Warburg's original hypothesis, damaged mitochondria are not at the root of the aerobic glycolysis exhibited by most tumor cells.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Introduction
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In the paper
“In this supply-based model, changes in metabolic fluxes occur in primary response to growth factor signaling, independent of changes in ATP and other mechanisms worked out by early biochemists (Figure 2B).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Altered metabolism is a direct response to growth factor signaling
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In the paper
“Most tumor mitochondria are not defective in their ability to carry out oxidative phosphorylation.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Introduction
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In the paper
“But evidence for an alternative concept, that the primary functions of activated oncogenes and inactivated tumor suppressors are to reprogram cellular metabolism, has continued to build over the past several years.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Introduction
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In the paper
“Instead, in proliferating cells mitochondrial metabolism is reprogrammed to meet the challenges of macromolecular synthesis.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Introduction
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In the paper
“However, in proliferating cells, in contrast to quiescent cells, this oxidative phosphorylation-dependent production of ATP appears secondary to the use of mitochondrial enzymes in the synthesis of anabolic precursors.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Altered metabolism is a direct response to growth factor signaling
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In the paper
“However, the PI3K/Akt pathway also promotes glucose carbon flux into biosynthetic pathways that rely upon functional mitochondrial metabolism (Figure 3).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > PI3K/Akt/mTORC1 activation: driving anabolic metabolism and tumorigenesis by reprogramming mitochondria
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In the paper
“The reprogramming of cellular metabolism towards macromolecular synthesis is critical to supplying enough nucleotides, proteins, and lipids for a cell to double its total biomass and then divide to produce two daughter cells.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Altered metabolism is a direct response to growth factor signaling
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In the paper
“In contrast to the catabolic metabolism of differentiated cells, this anabolic metabolism fundamental to cell growth and proliferation is not focused on maximizing ATP yield.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Altered metabolism is a direct response to growth factor signaling
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“Finally, a study isolating the cell-intrinsic consequences of mTORC1 activation demonstrated that SREBP-mediated de novo lipogenesis is a critical component of mTORC1-driven proliferation (Duvel et al., 2010).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > PI3K/Akt/mTORC1 activation: driving anabolic metabolism and tumorigenesis by reprogramming mitochondria
What the sources say
- Not checked yetcites Duvel et al., 2010 source
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“the lack of evidence that 2HG was acting as a mutagen (Mardis et al., 2009)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
What the sources say
- Not checked yetcites Mardis et al., 2009 source
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“AML samples with low to undetectable 2HG were subsequently sequenced and determined to be IDH1 and IDH2 wild-type”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Gross et al., 2010 source
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“There are cancers which do exhibit decreased flux of glucose-derived pyruvate into the mitochondria relative to normal tissues.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > HIF-1-mediated inhibition of carbon flux into mitochondria can be anti-proliferative
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In the paper
“Oncogenic mutations in proto-oncogenes can be selected for in tumor populations subjected to metabolic stress.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Did proto-oncogenes and tumor suppressors arise in evolution as components of metabolic regulation?
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“neomorphic mutations of IDH1 or IDH2 and TET2 loss-of-function mutations were found to be mutually exclusive in a large AML cohort”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
What the sources say
- Not checked yetcites Figueroa et al., 2010 source
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In the paper
“additional IDH mutations can produce 2HG (Ward et al., 2011)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Ward et al., 2011
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“shRNA knockdown of TET2 recapitulated the effect of IDH mutant overexpression on blocking hematopoietic cell differentiation (Figueroa et al., 2010)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
What the sources say
- Not checked yetcites Figueroa et al., 2010 source
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“multiple groups have found that IDH mutant expression and 2HG elevation can inhibit the TET family of enzymes that hydroxylate 5’-methylcytosine (Figueroa et al., 2010; Turcan et al., 2012; Xu et al., 2011)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
What the sources say
- Not checked yetcites Figueroa et al., 2010 source
- Not checked yetcites Turcan et al., 2012
- Not checked yetcites Xu et al., 2011
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“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).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
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In the paper
“The strongest evidence to date that altered metabolism is selected for by cancer cells during tumorigenesis has come with the recent elucidation of somatic mutations in metabolic enzymes.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Oncogenic mutations in metabolic enzymes: the discovery of IDH1 mutations and the oncometabolite 2-hydroxyglutarate
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In the paper
“Taken together, these findings demonstrate that the reprogramming of mitochondrial citrate metabolism is a central aspect of PI3K/Akt oncogenic activity.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > PI3K/Akt/mTORC1 activation: driving anabolic metabolism and tumorigenesis by reprogramming mitochondria
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In the paper
“Most cancers depend on these syntheses rather than exogenous supplies.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > PI3K/Akt/mTORC1 activation: driving anabolic metabolism and tumorigenesis by reprogramming mitochondria
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In the paper
“These data provide further evidence that reprogrammed glutamine metabolism is critical to the growth and survival of Myc-driven malignancies.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Myc activation also impacts mitochondrial metabolism
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“However, HIF-1 activation has the additional effect of inhibiting mitochondrial metabolism of glucose carbon, in part by promoting the expression of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit PDH activity (Kim et al., 2006; Papandreou et al., 2006).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > HIF-1-mediated inhibition of carbon flux into mitochondria can be anti-proliferative
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In the paper
“However, as will be discussed later in this review, these cancers still rely on mitochondrial metabolic flux.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > HIF-1-mediated inhibition of carbon flux into mitochondria can be anti-proliferative
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“serum 2HG levels have successfully correlated with IDH1 R132 mutations in AML”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Gross et al., 2010 source
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“recent data have suggested that 1H magnetic resonance spectroscopy can be applied for 2HG detection in vivo for glioma (Andronesi et al., 2012; Choi et al., 2012; Gross et al., 2010; Pope et al., 2012)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
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In the paper
“TET2 mutant AML samples displayed an overlapping DNA hypermethylation signature with samples having IDH1 or IDH2 mutations”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
What the sources say
- Not checked yetcites Figueroa et al., 2010 source
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In the paper
“However, other studies have added further strength to the concept that reduced pyruvate kinase enzymatic activity in the cytoplasm, leading to enhanced anabolic metabolism from glycolytic intermediates, is the primary role for PKM2 expression in proliferating cells.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The primary role of PKM2 expression in proliferating cells is to facilitate anabolic metabolism
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“a small fraction of gliomas lacking IDH1 mutations were known to harbor mutations at IDH2 R172, the analogous residue to IDH1 R132 (Yan et al., 2009)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Yan et al., 2009 source
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In the paper
“These additional alleles may account for the recently described subset of 2HG-elevated chondrosarcoma samples that lacked the most common IDH1 or IDH2 mutations but were not examined for other IDH alterations (Amary et al., 2011).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Amary et al., 2011 source
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In the paper
“For example, proliferating cells almost universally express the M2 isoform of pyruvate kinase M (PKM2).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolic enzymes can be alternatively spliced to isoforms that support anabolic growth
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“The weight of the evidence now suggests that regulation of HIF-1 stability through decreased PHD2 activity is not the primary effect of IDH mutations (Chowdhury et al., 2011; Dang et al., 2009; Jin et al., 2011; Mardis et al., 2009; Metellus et al., 2011; Williams et al., 2011).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
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In the paper
“Oncogenic Myc has also been shown to promote the mitochondrial utilization of glutamine by enhancing the expression of glutaminase (GLS), which deamidates glutamine to glutamate.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Myc activation also impacts mitochondrial metabolism
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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 discovery provided additional evidence that 2HG production was the primary feature being selected for in tumors.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the finding that IDH mutations occurred early in disease progression (Watanabe et al., 2009)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
What the sources say
- Not checked yetcites Watanabe et al., 2009 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“Metabolic changes associated with proliferating cells do not simply occur passively in response to damaged mitochondria or changes in ATP levels.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Did proto-oncogenes and tumor suppressors arise in evolution as components of metabolic regulation?
plain- Asserted: passes — The authors put it forward as true.
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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 weight of the evidence to date supports the concept that reprogramming of cellular metabolism is a primary and fundamental aspect of transformation resulting from mutations in proto-oncogenes and tumor suppressors.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Did proto-oncogenes and tumor suppressors arise in evolution as components of metabolic regulation?
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Numerous reports have now highlighted the ability of 2HG to inhibit several α-ketoglutarate dependent dioxygenase enzymes (Figure 5).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
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In the paper
“the common feature of this remaining subset of 2HG-elevated AMLs was another mutation in IDH2, occurring at R140 (Ward et al., 2010)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Ward et al., 2010 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“several samples with elevated 2HG were found to have neomorphic mutations at either IDH1 R132 or IDH2 R172 (Gross et al., 2010)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Gross et al., 2010 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In place of oxidative metabolism of both glucose and glutamine, these cancers preferentially perform reductive and carboxylating biosynthetic reactions from glutamine carbon (Le et al., 2012; Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > HIF-1-mediated inhibition of carbon flux into mitochondria can be anti-proliferative
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In the paper
“a rare metabolite found at only trace amounts in mammalian cells under normal conditions (Dang et al., 2009)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Oncogenic mutations in metabolic enzymes: the discovery of IDH1 mutations and the oncometabolite 2-hydroxyglutarate
What the sources say
- Not checked yetcites Dang et al., 2009 source
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In the paper
“some 2HG-elevated AML samples lacked IDH1 R132 or IDH2 R172 mutations”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Ward et al., 2010 source
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In the paper
“By diverting pyruvate into lactate, HIF-1 blocks glucose carbon incorporation into mitochondrial citrate which is critical for lipid synthesis (Lum et al., 2007).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > HIF-1-mediated inhibition of carbon flux into mitochondria can be anti-proliferative
What the sources say
- Not checked yetcites Lum et al., 2007 source
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Proliferative metabolism is heavily dependent on the reprogramming of mitochondria to serve a synthetic rather than degradative role.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Did proto-oncogenes and tumor suppressors arise in evolution as components of metabolic regulation?
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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
“Current evidence suggests the decreased activity of PKM2 is selected to facilitate anabolic metabolism (Figure 4).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolic enzymes can be alternatively spliced to isoforms that support anabolic growth
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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, increased glycolytic metabolism from activated Ras does not stem from defective mitochondrial pathways.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Did proto-oncogenes and tumor suppressors arise in evolution as components of metabolic regulation?
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“the observed propensity of tumor cells to synthesize pentose phosphates through a G6PD-independent pathway (Boros et al., 2000; Zhao et al., 2010)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Boros et al., 2000
- Not checked yetcites Zhao et al., 2010 source
hedged- Asserted: passes — The authors put it forward as true.
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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 gliomas and chondrosarcomas there is no evidence of mutations in TET enzymes”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
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In the paper
“in human cells proliferating in hypoxia, α-ketoglutarate can accumulate and be metabolized through an enhanced reductive activity of wild-type IDH2 in the mitochondria, leading to 2HG accumulation in the absence of IDH mutation (Wise et al., 2011)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
- Not checked yetcites Wise et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“succinate has been shown to alter histone demethylase activity in yeast (Smith et al., 2007)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
- Not checked yetcites Smith et al., 2007 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“cohort studies have not detected a decrease in cancer incidence in G6PD-deficient men (Cocco et al., 1998; Ferraris et al., 1988)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Cocco et al., 1998 source
- Not checked yetcites Ferraris et al., 1988
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In the paper
“Subsequent work confirmed that fumarate could inhibit PHD2 (Isaacs et al., 2005)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
- Not checked yetcites Isaacs et al., 2005 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“there was a progressive accumulation of H3K9 methylation which preceded the increase in DNA methylation”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
What the sources say
- Not checked yetcites Lu et al., 2012
plaindirect- Asserted: passes — The authors put it forward as true.
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In the 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)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the mark most altered with stable, as opposed to transient, expression of IDH mutation is methylation at histone H3 lysine 9 (H3K9) (Lu et al., 2012)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
What the sources say
- Not checked yetcites Lu et al., 2012
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Recently three independent reports implicated IDH-dependent reductive carboxylation as playing a particularly important role in proliferating cells that exhibit decreased flux of glucose-derived pyruvate into the mitochondria. This occurs in hypoxic cells or in cells harboring defects in mitochondrial oxidative phosphorylation (Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“It would also fit with the importance of glucose carbon to be metabolized through other branches of glycolytic metabolism, including serine synthesis (as discussed above) and the hexosamine pathway (Wellen et al., 2010).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Wellen et al., 2010 source
hedged- Asserted: passes — The authors put it forward as true.
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In the 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)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“2HG can inhibit the prolyl hydroxylase that regulates collagen synthesis (Xu et al., 2011)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
What the sources say
- Not checked yetcites Xu et al., 2011
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“NADH can be converted to NADPH within the mitochondria via a transhydrogenase absent from the cytosol (Rydstrom, 2006)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Rydstrom, 2006 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“smaller case control studies have also failed to demonstrate a relationship (Forteleoni et al., 1988; Pisano et al., 1991)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“IDH2 R140 mutations now account for nearly half of all cases of this devastating disease (Kranendijk et al., 2010)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
- Not checked yetcites Kranendijk et al., 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Loss of function mutations in the TCA cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) have been known for several years to occur in pheochromocytoma, paraganglioma, leiomoyoma, and renal carcinoma.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“for many proliferating cells, the major problem is not how to maximize ATP yield, but rather how to maximize the flux of carbon into macromolecular synthetic pathways”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
plain- Asserted: passes — The authors put it forward as true.
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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
“knowledge regarding cellular redox suggests the reductive flux is likely to occur in the mitochondria”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Mitochondria have a high NADH:NAD+ ratio, particularly in hypoxia (Chance and Thorell, 1959; Frezza et al., 2011)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Chance and Thorell, 1959
- Not checked yetcites Frezza et al., 2011 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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 2HG-induced alterations in histone and DNA methylation are likely synergistic”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“and that succinate could also inhibit the related enzyme PHD3 (Lee et al., 2005)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
- Not checked yetcites Lee et al., 2005 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“in gliomas and chondrosarcomas IDH1 or IDH2 mutations have been linked with altered DNA methylation profiles (Noushmehr et al., 2010; Pansuriya et al., 2011; Turcan et al., 2012)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“cells with activated PI3K/Akt upregulate the activity of ENTPD5, an endoplasmic reticulum enzyme involved in glycosylation reactions and linked to ATP hydrolysis (Fang et al., 2010)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Fang et al., 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Neoplastic clones did not demonstrate preferential expression of the wild type G6PD allele.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Ferraris et al., 1988
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“inhibition of H3K9 demethylation by 2HG, or siRNA knockdown of an H3K9 demethylase, was sufficient to block cell differentiation in the absence of changes in DNA methylation”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
What the sources say
- Not checked yetcites Lu et al., 2012
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
“Unlike ATP, cytosolic NADPH might be limiting for cell proliferation.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: unclear — It is unclear why the paper says it holds.
In the paper
“researchers looked for and successfully found germline IDH2 R140 mutations in D-2HG aciduria”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
- Not checked yetcites Kranendijk et al., 2010 source
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.
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In the paper
“Succinate was initially found to impair PHD2, the α-ketoglutarate-dependent enzyme regulating HIF stability, through product inhibition (Selak et al., 2005).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
What the sources say
- Not checked yetcites Selak et al., 2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“These studies focused on men with the Mediterranean variant of G6PD, an allele demonstrating severe enzyme deficiency with less than 10 percent of normal activity.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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 observations linked the elevated HIF levels observed in SDH and FH deficient tumors to the activity of the succinate and fumarate metabolites.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
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.
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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 inhibition could impact the tumor microenvironment and partly account for the diffuse nature of lower-grade gliomas.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“IDH-dependent reductive carboxylation of α-ketoglutarate to isocitrate was described in early metabolic literature (Ochoa, 1948)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Ochoa, 1948 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
“Data now support the concepts that altered metabolism results from active reprogramming by altered oncogenes and tumor suppressors”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
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: unclear — It is unclear why the paper says 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
“and that metabolic adaptations can be clonally selected during tumorigenesis”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
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: unclear — It is unclear why the paper says it holds.
- Probably not a substantial claim. 12
- It may state two separate claims as one. 14
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
“Activation of the PI3K/Akt pathway is perhaps the most common lesion in spontaneous human cancers.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > PI3K/Akt/mTORC1 activation: driving anabolic metabolism and tumorigenesis by reprogramming mitochondria
hedged- 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.
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
“It has become clear that anabolic metabolism is under complex regulatory control directed by growth factor signal transduction in non-transformed cells.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Introduction
boosteddirect- 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 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
“Both of these findings are consistent with PKM2 primarily acting as a glycolytic switch that can be rapidly inactivated in tumor cells by multiple mechanisms, all of which facilitate the shunting of glucose carbon/glycolytic intermediates into branching anabolic pathways.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The primary role of PKM2 expression in proliferating cells is to facilitate anabolic metabolism
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
“IDH1 mutations at R132 are not simply loss-of-function for isocitrate and α-ketoglutarate interconversion, but also acquire a novel reductive activity to convert α-ketoglutarate to 2-hydroxyglutarate (2HG)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Oncogenic mutations in metabolic enzymes: the discovery of IDH1 mutations and the oncometabolite 2-hydroxyglutarate
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.
It may state two separate claims as one.
In the paper
“In both cell types, the overexpression of IDH mutants blocked acquisition of mature myeloid markers while increasing the expression of stem cell markers (Figueroa et al., 2010).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Metabolites as oncogenes: dysregulating epigenetics and cellular differentiation
What the sources say
- Not checked yetcites Figueroa et al., 2010 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.
It may state two separate claims as one.
In the paper
“Metabolite screening approaches can also distinguish neomorphic IDH mutations from SNPs and sequencing artifacts with no effect on IDH enzyme activity, as well as from an apparently rare subset of loss-of-function, non 2HG-producing IDH mutations”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is a biomarker and common feature of both IDH1 and IDH2 mutations
What the sources say
- Not checked yetcites Ward et al., 2011
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.
None of the sources cited for this claim have been checked yet.
In the paper
“Cells expressing oncogenic Myc are glutamine-addicted and undergo apoptosis when glutamine is withdrawn from the culture medium.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Myc activation also impacts mitochondrial metabolism
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.
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 raise the possibility that significant flux through G6PD to generate NADPH is not necessarily critical for cell proliferation or tumorigenesis”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
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.
Probably not a substantial claim.
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
“Historically, the oxidative pentose phosphate pathway, branching off glycolysis at glucose-6-phosphate dehydrogenase (G6PD), has been considered the major NADPH producing pathway.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
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.
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
“It is critical for providing reducing equivalents for fatty acid and cholesterol biosynthesis, as well as for modulating oxidative stress.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating 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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. 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 findings could all be correct if a mitochondrial-cytosolic NADPH shuttle exists using these enzymes (Figure 6).”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent work has revisited how proliferating cells maintain glycolytic flux by either minimizing ATP production or enhancing ATP consumption.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating 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.
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
“Perhaps elevated succinate and fumarate resulting from SDH and FH mutations can promote tumorigenesis in part through epigenetic modulation.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
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.
Probably not a substantial claim.
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 findings provide further evidence that IDH mutation can impair differentiation in non-transformed cells from multiple cells of origin, and that this impairment is linked to 2HG-mediated epigenetic dysregulation.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
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.
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
“The ability of 2HG to alter epigenetics may reflect its evolutionary ancient status as a signal for elevated glutamine/glutamate metabolism and/or oxygen deficiency.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > 2HG is not the only oncometabolite
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no 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
“Alternatively, other chromatin-modifying α-ketoglutarate dependent dioxygenase enzymes may be inhibited by 2HG in these cells.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > The oncometabolite 2HG does more than inhibit TET activity and DNA demethylation
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.
Probably not a substantial claim.
In the paper
“In this alternative pathway, the high-energy phosphate of PEP is not transferred to ADP, but instead to a histidine residue on an upstream glycolytic enzyme. This alternative transfer therefore decouples the PEP→pyruvate conversion from ATP production.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Vander Heiden et al., 2010
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
“glycolysis in proliferating cells is limited by the rate of ATP consumption and not ATP production, as glycolytic enzymes can be inhibited when ATP levels are high (Scholnick et al., 1973)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Textbook biochemical pathways often do not apply to proliferating cells
What the sources say
- Not checked yetcites Scholnick et al., 1973
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.
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
“Even within one subcellular compartment, there may be distinct pools of metabolites resulting from channeling between metabolic enzymes.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
hedgedconditional- 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.
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
“many obstacles remain such as cellular compartmentalization and the reliance of most cell culture on complex, incompletely defined media.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
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.
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
“we remain unable to reliably distinguish cytosolic metabolites from those in the mitochondria and other compartments. Current fractionation methods often lead to metabolite leakage.”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
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.
In the paper
“some tumors may exhibit a symbiosis between lactate-producing cells and lactate-consuming cells (Sonveaux et al., 2008)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
What the sources say
- Not checked yetcites Sonveaux et al., 2008
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.
In the paper
“lactate produced by tumor cells can acidify the surrounding microenvironment and potentially promote tumor invasion”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
What the sources say
- Not checked yetcites Sonveaux et al., 2008
hedgedconditional- 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
“fatty acid exchange between omental adipocytes and ovarian carcinoma cells has been documented (Nieman et al., 2011)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
What the sources say
- Not checked yetcites Nieman et al., 2011
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: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“critical fluxes have been quantified in cultured cancer cells and methods for these analyses continue to improve (DeBerardinis et al., 2007; Mancuso et al., 2004; Yuan et al., 2008)”
§ Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate > Challenges ahead for studying the metabolic hallmark of cancer
What the sources say
- Not checked yetcites DeBerardinis et al., 2007 source
- Not checked yetcites Mancuso et al., 2004
- Not checked yetcites Yuan et al., 2008
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.
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 cited source says what the claim attributes to it.
In the citing paper
“The evidence for the necessity of glutamine for cancer progression is conflicted: some studies have reported that tumours can grow well without glutamine [66,67], while others showed that cancers are glutamine-addicted [68,69,70].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [68]
In the citing paper
“The previous paradigm of metabolic regulation argued that metabolic pathways were exclusively controlled through allosteric regulation of metabolic enzymes, either by ATP levels or metabolites themselves (the reactive model) (40).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [40]
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
Self-citationAn Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
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-citationKim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905
Otto Warburg's contributions to current concepts of cancer metabolism
Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3038 · Cited by 3,427
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766
Self-citation
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- Turcan, 2012, Nature
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Cited by
Sorted by citations
The Warburg Effect: How Does it Benefit Cancer Cells?
Liberti, M. V., & Locasale, J. W. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.12.001 · Cited by 5,150
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R. M., Ferrone, C. R., Mullarky, E., Shyh-Chang, N., et al. (2013) · Nature · doi:10.1038/nature12040 · Cited by 1,990
Zielonka, J., Joseph, J., Sikora, A., Hardy, M., Ouari, O., Vasquez-Vivar, J., Cheng, G., Lopez, M., & Kalyanaraman, B. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00042 · Cited by 1,683
Serine, glycine and one-carbon units: cancer metabolism in full circle
Locasale, J. W. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3557 · Cited by 1,727
Metadata
- Authors
- Ward, P. S., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Thompson, Craig B.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 21
- Issue
- 3
- Pages
- 297-308
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3311998
- OpenAlex
- W2052543023
- Semantic Scholar
- 9802ecaa29613434cd7f6f7fa0e72b84a26c9d29
- Cited by
- 3,233
- References
- 145
- Citations by year
- 2026: 149 · 2025: 170 · 2024: 216 · 2023: 204 · 2022: 269 · 2021: 271 · 2020: 295 · 2019: 244 · 2018: 256 · 2017: 235 · 2016: 213 · 2015: 248 · 2014: 228 · 2013: 169 · 2012: 63
- FWCI
- 17.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 994 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- cancer metabolism, metabolic reprogramming, aerobic glycolysis, Warburg effect, anabolic metabolism, signal transduction, cell differentiation, cancer hallmarks, mitochondrial damage
- MeSH terms
- Cell Differentiation, Humans, Isoenzymes, Mitochondria, Models, Biological, Neoplasms, Biomarkers, Tumor, Signal Transduction, Proto-Oncogene Proteins c-myc, Alternative Splicing, Evolution, Molecular, Epigenesis, Genetic, 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 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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