Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

Loss of CAR inhibits NAFLD-induced hepatocarcinogenesis.

“while loss of constitutive androstane receptor (CAR), a well-known liver tumor promoter that mediates toxic bile acid signaling, inhibits NAFLD-induced hepatocarcinogenesis.”

May combine two claims.

The majority of metabolites studied displayed robust circadian rhythms in control WT mice but were deregulated in jet-lagged WT mice.

“The majority of metabolites studied displayed robust circadian rhythms in control WT mice, but were deregulated in jet-lagged WT mice.”

May combine two claims.

Under entrained condition, Per- or Cry-mutants developed fewer but larger HCCs first detected at 50 weeks, while Albcre;Bmal1fl/fl mice developed a large number but small HCCs first detected after 70 weeks.

“Under entrained condition, Per- or Cry-mutants developed fewer but larger HCCs first detected at 50 weeks of age, while Albcre;Bmal1fl/fl mice developed a large number but small HCCs first detected after 70 weeks of age.”

May combine two claims.

Unirradiated jet-lagged WT and mutant mice displayed similar risk of lymphoma and HCC regardless of differences in molecular signatures of liver clock disruption, with HCC incidence specific to each mouse model by 90 weeks.

“unirradiated jet-lagged WT and mutant mice displayed similar risk of lymphoma and HCC regardless of the differences in the molecular signatures of liver clock disruption in these mice, with HCC incidence specific to each mouse model by 90 weeks of age (Figures 1C, 1D and Table 1).”

May combine two claims.

Jet-lagged WT mice displayed increased serum and hepatic levels of lactate and pyruvate, coupled with elevated levels of essential bioprecursors for amino acids, nucleotides, triglyceride and cholesterol synthesis, such as α-ketoglutarate, glycerol 3 phosphate, glutamine, ribose 5 phosphate, acetyl CoA, malate and fumarate.

“jet-lagged WT mice displayed increased serum and hepatic levels of lactate and pyruvate, coupled with elevated levels of essential bioprecursors for amino acids, nucleotides, triglyceride and cholesterol synthesis, such as α-ketoglutarate, glycerol 3 phosphate, glutamine, ribose 5 phosphate, acetyl CoA, malate and fumarate, etc.”

May combine two claims.

These metabolic changes were associated with deregulation of fatty acid transporting carnitines and accumulation of TCA cycle intermediates (isocitrate, succinate, fumarate and malate), indicating mitochondrial electron transport chain disruption and redox deregulation.

“These were associated with deregulation of fatty acid transporting carnitines and accumulation of TCA cycle intermediates, such as isocitrate, succinate, fumarate and malate, an indication of mitochondrial electron transport chain disruption and redox deregulation (Figures 3 and S4–5).”

May combine two claims.

Major cancer types in mutant and jet-lagged mice include pancreatic and ovarian tumors, B-lymphoma and HCC, with lymphoma and HCC as the leading causes of cancer-related early euthanization.

“The major cancer types diagnosed in mutant and jet-lagged mice include pancreatic and ovarian tumors, B-lymphoma and HCC (Figures 1B and S1A), with lymphoma and HCC as the leading cause of cancer-related early euthanization.”

May combine two claims.

Both sexes of mutant mice displayed increased risk of hepatocarcinogenesis, with males showing greater HCC risk than females.

“Both sexes of mutant mice displayed increased risk of hepatocarcinogenesis, with males showed greater HCC risk than females.”

May combine two claims.

Ablation of FXR dramatically increases enterohepatic bile acid levels and jet lag-induced HCC.

“Ablation of farnesoid X receptor (FXR) dramatically increases enterohepatic bile acid levels and jet lag-induced HCC, while loss of constitutive androstane receptor (CAR), a well-known liver tumor promoter that mediates toxic bile acid signaling, inhibits NAFLD-induced hepatocarcinogenesis.”

May combine two claims.

Jet-lagged WT mice displayed decreased serum triglycerides and free fatty acids and increased hepatic triglycerides and free fatty acids.

“jet-lagged WT mice also displayed a decrease in serum triglycerides and free fatty acids coupled with an increase in hepatic level of triglycerides and free fatty acids.”

May combine two claims.

Jet-lagged WT mice exhibited hepatomegaly, increased bile duct proliferation, chronic liver inflammation, accelerated hepatocyte proliferation and death, and fibrosis long before HCC detection.

“This is accompanied by hepatomegaly (Figure 2D), increased bile duct proliferation and chronic liver inflammation (Figure 2E), accelerated hepatocyte proliferation and death, and the appearance of fibrosis long before HCC detection (Figure 2F).”

May combine two claims.

Diseases in jet-lagged mice include neurodegeneration, severe ulcerative dermatitis, aging, cystic renal dysplasia, and cancer.

“which include neurodegeneration, severe ulcerative dermatitis, aging, cystic renal dysplasia, and cancer (Table 1).”

May combine two claims.

Chronic jet lag increased both numbers and sizes of tumors in Per and Cry mutants and also the size of tumor in HCC-bearing Albcre;Bmal1fl/fl mice.

“Chronic jet lag increased both numbers and sizes of tumors in Per and Cry mutants and also the size of tumor in HCC bearing Albcre;Bmal1fl/fl mice (Figures 1B, S1A–B and Table 1).”

May combine two claims.

Under entrained conditions, Car−/− mice had an intact liver clock and maintained a circadian profile of FXR and Cyp7A1 expression.

“Under entrained conditions, Car−/− mice had an intact liver clock and maintained a circadian profile of FXR and Cyp7A1 expression (Figures 6A–B).”

May combine two claims.

Ablation of all three β-adrenergic receptors in mice completely inhibited AP1 and pCREB nuclear accumulation and also Car, Fos, Myc, and Cyp2b10 expression in mouse livers under both entrained and jet lag conditions.

“Ablation of all three β-adrenergic receptors in mice (β-less) completely inhibited AP1 and pCREB nuclear accumulation and also Car, Fos, Myc and Cyp2b10 expression in mouse livers under both entrained and jet lag conditions (Figures 7F–G)”

The quote only partly states this claim.

The inhibition in β-less mice was associated with strong HCC resistance.

“which was associated with strong HCC resistance (Figure S8A).”

May combine two claims. The quote only partly states this claim.

The gene deregulation includes overexpression of genes promoting lipid, amino acid and nucleotide biosynthesis and storage, cytoplasmic glycolysis, glycogenolysis, oxidative stress, hepatocyte proliferation and death, cholestasis, and fibrosis; suppression of genes stimulating fatty acid mitochondrial transportation and β-oxidation, glycogen synthesis, and tumor suppression; and deregulation of基因s

“This includes overexpression of genes promoting lipid, amino acids and nucleotides biosynthesis and storage, cytoplasmic glycolysis, glycogenolysis, oxidative stress, hepatocyte proliferation and death, cholestasis, and fibrosis, suppression of genes stimulating fatty acid mitochondria transportation and β-oxidation, glycogen synthesis, and tumor suppression, and deregulation of genes controlling”

May combine two claims.

In livers of Albcre;Bmal1fl/fl mice, Per2 mRNA still displayed a shifted and dampened circadian expression profile, while Cry1 mRNA was constitutively overexpressed.

“Surprisingly, in the livers of Albcre;Bmal1fl/fl mice, Per2 mRNA still displayed a shifted and dampened circadian expression profile, while Cry1 mRNA was constitutively overexpressed.”

May combine two claims.

In jet-lagged wild-type and circadian gene mutant mice, FXR was suppressed and CAR was induced.

“Among these nuclear receptors, the suppression of FXR and induction of CAR, as reported for human HCC (Hoshida et al., 2008; Lee et al., 2006), were found in jet-lagged WT and circadian gene mutant mice”

May combine two claims.

Unlike in mouse thymus where circadian disruption suppresses p53, chronic jet lag induced coupled activation of p53 and c-Myc in livers of WT mice at a young age.

“However, unlike in mouse thymus where circadian disruption is sufficient to suppress p53 (Lee et al., 2010), chronic jet lag induced a coupled activation of p53 and c-Myc in the livers of WT mice at a young age.”

• cites Lee et al., 2010 sourceNot checked yet

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May combine two claims.

Human and mouse CAR promoters contain conserved AP1 and CRE motifs potentially activated by SNS signaling, in addition to multiple D- and E-boxes potentially recognized by DBP and BMAL1/CLOCK.

“We found that apart from multiple D- and E-boxes potentially recognized by DBP and BMAL1/CLOCK, human and mouse CAR promoters contain conserved AP1 and CRE motifs potentially activated by SNS signaling (Figures 7A).”

May combine two claims.

Binding of BMAL1 or c-FOS and pCREB to Per1 and Car promoters was not detected in livers of Albcre;Bmal1fl/fl or β-less mice, respectively.

“As expected, the binding of BMAL1 or c-FOS and pCREB to Per1 and Car promoters was not detected in livers of Albcre;Bmal1fl/fl or β-less mice, respectively (Figure 7H).”

May combine two claims.

The complex liver pathology in jet-lagged wild-type mice is driven by global hepatic gene deregulation detectable soon after jet lag initiation, with a pattern overlapping significantly with a human HCC transcriptomic signature, including induction of Trp53, Myc, and β-catenin.

“The complex liver pathology in jet-lagged WT mice is driven by global hepatic gene deregulation, which can be detected soon after the initiation of jet lag and displays a pattern overlapping significantly with a human HCC transcriptomic signature, including the induction of key human HCC molecular markers such as Trp53, Myc and β-catenin.”

May combine two claims.

c-FOS binding to the Per1 promoter displayed a strong circadian rhythm peaking at ZT2, while its binding to the Car promoter was constitutively low.

“Although c-FOS binding to the Per1 promoter displayed a strong circadian rhythm and peaked at ZT2, its binding to Car promoter was constitutively low.”

May combine two claims.

Jet lag induces a global shift in liver metabolism in mice that promotes fat synthesis and storage via accelerated cytoplasmic glycolysis and increases oxidative stress and synthesis of bioprecursors supporting rapid cell division.

“We show that jet lag induces a global shift in liver metabolism in mice, which not only promotes fat synthesis and storage via accelerated cytoplasmic glycolysis but also increases oxidative stress and the synthesis of bioprecursors supporting rapid cell division.”

May combine two claims.

In livers of jet-lagged wild-type mice, CAR mRNA and protein were arrhythmic and elevated at most times, accompanied by constitutive overexpression of Cyp2b10 mRNA.

“but were arrhythmic and elevated at most times in the livers of jet-lagged WT mice, coupled with constitutive overexpression of Cyp2b10 mRNA, a direct consequence of CAR-directed transcriptional activation (Figure 6E).”

May combine two claims.

Car−/− mice were prone to NAFLD, circadian disruption-induced cholestasis, and glycogen storage disease.

“although Car−/− mice were also prone to NAFLD and circadian disruption-induced cholestasis and glycogen storage disease”

May combine two claims.

Bmal1 and Dbp were both suppressed by circadian disruption.

“However, Bmal1 and Dbp were both suppressed by circadian disruption (Figures 1C–D and 4C).”

May combine two claims.

Chronic jet lag abolished BMAL1 binding to both Car and Per1 promoters, significantly dampened c-FOS and pCREB interaction with the Per1 promoter, and induced a coupled, dramatically increased binding of c-FOS and pCREB to the Car promoter at all times studied.

“Chronic jet lag abolished BMAL1 binding to both Car and Per1 promoters, significantly dampened c-FOS and pCREB interaction with the Per1 promoter, but induced a coupled and dramatically increased binding of c-FOS and pCREB to the Car promoter at all times studied (Figure 7H)”

May combine two claims.

In addition to leptin resistance, circadian dysfunction induces hyperinsulinemia, hyperglycemia, dyslipidemia at the organismal level, and liver metabolic disorders including NAFLD.

“We found that in addition to leptin resistance, circadian dysfunction also induces hyperinsulinemia, hyperglycemia and dyslipidemia at the organismal level and liver metabolic disorders including NAFLD.”

May combine two claims.

Car−/− mice showed a dramatically decreased risk of jet lag-induced hepatomegaly, inflammation, hepatocyte proliferation, necrosis, and fibrosis.

“they showed a dramatically decreased risk of jet lag induced hepatomegaly, inflammation, hepatocyte proliferation and necrosis, fibrosis”

May combine two claims.

In jet-lagged wild-type and circadian gene mutant mice, β-catenin, c-Myc, SREBP1, PPARγ, Cyp2B10, and Cyp7A1 were upregulated.

“coupled with upregulation of transcription factors stimulating cell proliferation and steatosis such as β-catenin, c-Myc, SREBP1 and PPARγ (encoded by the Nr1c3), as well as Cyp2B10, a direct target of CAR activation, and Cyp7A1, the rate limiting enzyme for bile acid synthesis negatively regulated by FXR (Figures 4D–F and S6A–D).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The findings on Cry1 mRNA overexpression in Albcre;Bmal1fl/fl mice are consistent with a previous report and with the finding that PER2 and CRY1 proteins still display robust circadian expression in these mice under entrained condition.

“These findings were consistent with a previous report on Cry1 mRNA hepatic overexpression in Albcre;Bmal1fl/fl mice (Lamia et al., 2008), and with our finding that the negative loop proteins PER2 and CRY1 still display a robust circadian expression in the livers of these mice under entrained condition (Figures 1C–D and 4C).”

• cites Lamia et al., 2008 sourceNot checked yet

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May combine two claims.

In wild-type mouse livers, nuclear accumulation of AP1 and pCREB is lowest at ZT6, slightly elevated at ZT2, and peaks at ZT18.

“while nuclear accumulation of AP1 and pCREB is lowest at ZT6, slightly elevated at ZT2 and peaks ZT18 (Figures 7D–E).”

May combine two claims.

Car−/− mice lacked nuclear β-catenin activation and had dramatically dampened c-Myc and Cyp2B10 protein expression in the liver.

“However, they lacked β-catenin nuclear activation and showed dramatically dampened c-Myc and Cyp2B10 protein expression in the liver (Figures 6B–D).”

May combine two claims.

In vitro, the Car promoter was moderately stimulated by low levels of AP1 or CREB expression but suppressed by higher levels.

“In vitro transfection assays showed that the Car promoter was moderately stimulated by low levels but suppressed by higher levels of AP1 or CREB expression.”

May combine two claims.

Ablation of Car completely inhibited nuclear β-catenin expression and suppressed jet lag-induced activation of oncogenic, steatotic, and inflammatory genes, leading to strong HCC resistance.

“Ablation of Car completely inhibited nuclear β-catenin expression and suppressed jet lag induced activation of oncogenic, steatotic and inflammatory genes, leading to strong HCC resistance.”

May combine two claims.

Chronic jet lag promotes sympathetic dysfunction and peripheral clock disruption.

“We found that chronic jet lag promotes sympathetic dysfunction and peripheral clock disruption”

May combine two claims.

Jet lag activated CAR, measured by constitutive overexpression of the CAR target gene Cyp2b10 over a 24-hour period, and this was coupled with β-catenin and c-Myc overexpression.

“Jet lag activated CAR, as measured by constitutive overexpression of the CAR target gene Cyp2b10 over a 24 hr period, was coupled with β-catenin and c-Myc overexpression.”

May combine two claims.

Loss of FXR increases intrahepatic bile acid levels and stimulates hepatocarcinogenesis.

“and loss of FXR increases intrahepatic bile acid levels and stimulates hepatocarcinogenesis”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). May combine two claims.

Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction.

“Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction.”

Probably not a substantial claim: may not pass S3 (load-bearing).

SNS dysfunction is closely associated with metabolic syndrome, oncogenic activation, neoplastic growth and tumor initiation.

“SNS dysfunction is closely associated with metabolic syndrome, oncogenic activation, neoplastic growth and tumor initiation (Lee et al., 2010; Magnon et al., 2013; Tentolouris et al., 2006).”

• cites Lee et al., 2010 sourceNot checked yet

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• cites Magnon et al., 2013 sourceNot checked yet

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• cites Tentolouris et al., 2006 sourceNot checked yet

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May combine two claims.

Chronic circadian disruption increases tumor incidence and accelerates tumor progression.

“Thus, chronic circadian disruption not only increases tumor incidence but also accelerates tumor progression.”

May combine two claims.

CAR activation is strongly linked to β-catenin activation or mutation, a common molecular lesion in human HCC.

“which is strongly linked to β-catenin activation or mutation (Loeppen et al., 2002), a common molecular lesion in human HCC (Zucman-Rossi et al., 2015).”

• cites Loeppen et al., 2002Not checked yet

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• cites Zucman-Rossi et al., 2015 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The prevalence of obesity and NAFLD is coupled with an epidemic of chronic circadian disruption, also called social jet lag.

“The prevalence of obesity and NAFLD in our society is coupled with the epidemic of chronic circadian disruption, also termed “social jet lag” (Roenneberg et al., 2012).”

• cites Roenneberg et al., 2012 sourceNot checked yet

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May combine two claims.

Mutations in both Per1 and Per2 or phase-shifts of the liver clock by restricted feeding promote cholestasis and disrupt xenobiotic metabolism in mice.

“We have previously reported that mutations in both Per1 and Per2 or phase-shifts of the liver clock by restricted feeding both promote uncontrolled intrahepatic bile acid accumulation (cholestasis) and disrupt xenobiotic metabolism in mice (Ma et al., 2009)”

• cites Ma et al., 2009Not checked yet

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May combine two claims.

This global metabolic shift is coupled with elevated intracellular oxidative stress that induces liver damage and increased biosynthetic intermediates that support rapid cell division, a pattern reminiscent of cancer cells.

“This is also coupled with elevated intracellular oxidative stress that induces liver damage and increased biosynthetic intermediates that support rapid cell division (Figures 1E–F, 2A–B, S1C, S2 and S4–5), a pattern of metabolic adaptation closely reminiscent of that well-characterized for most types of cancer cells (Warburg, 1956).”

• cites Warburg, 1956 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Excessive fat accumulation induces liver injury, inflammation and regeneration, and progresses to NASH in a fraction of patients.

“Excessive fat accumulation induces liver injury, inflammation and regeneration, which progresses to non-alcoholic steatohepatitis (NASH) in a fraction of patients.”

• cites Michelotti et al., 2013 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NAFLD-induced HCC is predominantly diagnosed in males, but at older ages and earlier disease stages.

“Like HCC caused by other risk factors, NAFLD-induced HCC is predominantly diagnosed in males, but at older ages and earlier disease stages (Hashimoto et al., 2009).”

• cites Hashimoto et al., 2009 sourceNot checked yet

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May combine two claims.

Chronic circadian misalignment is sufficient to disrupt the liver clock and induce NAFLD-related HCC in WT mice.

“Together, these findings demonstrates that chronic circadian misalignment is sufficient to disrupt liver clock and induce NAFLD-related HCC in WT mice.”

Classified as probably not a substantial claim. May combine two claims.

Bile acids act as ligands for FXR, which indirectly suppresses Cyp7A1, the rate-limiting enzyme in bile acid biosynthesis.

“bile acids act as ligands for the farnesoid X receptor (FXR, NR1H4), which then indirectly suppresses Cyp7A1, the rate limiting enzyme in bile acid biosynthesis (Goodwin et al., 2000).”

• cites Goodwin et al., 2000 sourceNot checked yet

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Classified as probably not a substantial claim.

CAR activation is the basis for phenobarbital-promoted non-genotoxic or mutagen-induced hepatocarcinogenesis in mice.

“CAR activation is the basis for phenobarbital promoted non-genotoxic or mutagen-induced hepatocarcinogenesis in mice (Huang et al., 2005; Yamamoto et al., 2004)”

• cites Huang et al., 2005 sourceNot checked yet

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• cites Yamamoto et al., 2004 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Combined pharmacologic activation of CAR and genetic activation of β-catenin in mice is sufficient to induce liver tumors sharing an extensive gene expression signature with a subset of human HCC displaying β-catenin activation.

“We have recently shown that combined pharmacologic activation of CAR and genetic activation of β-catenin in mice is sufficient to induce liver tumors that share an extensive gene expression signature with a subset of human HCC displaying β-catenin activation (Dong et al., 2015).”

• cites Dong et al., 2015 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

HCC is the second most commonly observed malignancy in circadian gene-mutant mouse models.

“HCC is the second most commonly observed malignancy in circadian gene-mutant mouse models (Lee et al., 2010).”

• cites Lee et al., 2010 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Co-existence of NASH with leptin resistance and cholestasis significantly accelerates liver fibrosis.

“The co-existence of NASH with other metabolic disorders such as leptin resistance and cholestasis significantly accelerates liver fibrosis (Wang et al., 2010).”

• cites Wang et al., 2010 sourceNot checked yet

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Classified as probably not a substantial claim.

The liver is a focus of circadian regulation of metabolic pathways, especially those controlling glucose, lipid, cholesterol and bile acid synthesis and metabolism.

“The liver is the focus of circadian regulation of metabolic pathways, especially those controlling the synthesis and metabolism of glucose, lipid, cholesterol and bile acid (Bass and Takahashi, 2010).”

• cites Bass and Takahashi, 2010 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

NAFLD is predicted to become the leading cause of HCC in the 21st century as a secondary consequence of the obesity pandemic.

“non-alcoholic fatty liver disease (NAFLD) is predicted to become the leading cause of HCC in the 21st century as a secondary consequence of the obesity pandemic (Siegel and Zhu, 2009).”

• cites Siegel and Zhu, 2009 sourceNot checked yet

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May combine two claims.

Ablation of Fxr promotes cholestasis, NAFLD, NASH and HCC in mice.

“Ablation of Nr1h4 (hereafter referred to as Fxr) not only promotes cholestasis but also NAFLD, NASH and HCC in mice (Kim et al., 2007; Lu et al., 2000; Wang et al., 2008; Watanabe et al., 2004; Yang et al., 2007).”

• cites Kim et al., 2007 sourceNot checked yet

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• cites Lu et al., 2000Not checked yet

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• cites Wang et al., 2008 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

No oncogene addiction loops specific to NAFLD-induced HCC have been identified.

“Despite the impending burden of NAFLD-induced HCC, no oncogene addiction loops specific to this disease have been identified (Villanueva et al., 2013).”

• cites Villanueva et al., 2013 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Chronic circadian disruption is sufficient to induce leptin resistance in mice independent of diet choice and the time or amount of food intake.

“We have reported recently that chronic circadian disruption is sufficient to induce Leptin resistance in mice independent of diet choice and the time or amount of food intake (Kettner et al., 2015).”

• cites Kettner et al., 2015 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NASH and advanced fibrosis increase HCC risk by 15-fold and 25-fold in humans, respectively.

“NASH and advanced fibrosis increase HCC risk by 15 and 25 folds in humans, respectively (Guzman et al., 2008; Hashimoto et al., 2009).”

• cites Guzman et al., 2008 sourceNot checked yet

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• cites Hashimoto et al., 2009 sourceNot checked yet

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May combine two claims.

FXR inhibits steatosis and inflammatory genes.

“FXR also plays a broad role in liver function by inhibiting steatosis and inflammatory genes (Lopez-Velazquez et al., 2012).”

• cites Lopez-Velazquez et al., 2012Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Chronic jet lag significantly increases the risk of γ-radiation-induced cancer in mice.

“We have previously reported that chronic jet lag significantly increases the risk of γ-radiation induced cancer in mice (Lee et al., 2010).”

• cites Lee et al., 2010 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Lifestyle changes, rather than germline mutations, drive increased cancer risk in modern societies.

“Lifestyle changes, but not germline mutations, drive increased cancer risk in modern societies (Anand et al., 2008).”

• cites Anand et al., 2008 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

This finding agrees with previous reports that complete loss of p53 function is associated with progression but not initiation of hepatitis B virus or aflatoxin B1-induced HCC in humans.

“This finding agrees with previous reports that the complete loss of p53 function is associated with the progression but not initiation of hepatitis B virus or aflatoxin B1-induced HCC in humans (Hosono et al., 1993; Nose et al., 1993).”

• cites Hosono et al., 1993Not checked yet

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• cites Nose et al., 1993 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Combined systemic and liver metabolic disorders are frequently observed among human night-shift workers.

“Such combined systemic and liver metabolic disorders are also frequently observed among human night-shift workers (Zimberg et al., 2012).”

• cites Zimberg et al., 2012 sourceNot checked yet

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May combine two claims.

Bile acids can induce hepatocyte injury, mitochondrial damage, oxidative stress, DNA damage, and hepatocyte necrosis and apoptosis, which drive progression from NAFLD to NASH, fibrosis, and HCC.

“First, as strong hydrophobic detergents, bile acids can induce hepatocyte injury, mitochondrial damage, oxidative stress, DNA damage, and hepatocyte necrosis and apoptosis, all of which drive the progression of NAFLD to NASH, fibrosis and HCC (Audard et al., 2007; Perez and Briz, 2009).”

• cites Audard et al., 2007 sourceNot checked yet

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• cites Perez and Briz, 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Chronic social jet lag is one of the major lifestyle changes.

“One of the major lifestyle changes is chronic social jet lag (Roenneberg, 2013).”

• cites Roenneberg, 2013 sourceNot checked yet

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May combine two claims.

Jet lag-induced sympathetic dysfunction and peripheral clock suppression are sufficient to promote AP1 and CREB oncogenic activation independent of somatic mutations, driving Car overexpression throughout a 24-hour period to mediate persistent toxic bile acid signaling in jet-lagged wild-type mice.

“We demonstrated that jet lag induced sympathetic dysfunction and peripheral clock suppression are sufficient to promote AP1 and CREB oncogenic activation independent of somatic mutations, which drives Car overexpression throughout a 24 hr period to mediate persistent toxic bile acid signaling in jet-lagged WT mice.”

May combine two claims.

Together, these changes induce NAFLD and progression from NAFLD to HCC.

“Together, these induce NAFLD and also the progression from NAFLD to HCC.”

May combine two claims.

Inverse agonists to suppress human CAR and agonists to activate human FXR are both pharmaceutically available.

“Inverse agonists to suppress human CAR and agonists for activation of human FXR are both pharmaceutically available (Hirschfield et al., 2015; Huang et al., 2004).”

• cites Hirschfield et al., 2015 sourceNot checked yet

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• cites Huang et al., 2004 sourceNot checked yet

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Among top deregulated gene pathways, nuclear receptor CAR is constitutively activated by overexpression in response to SNS dysfunction and peripheral clock disruption and by transactivation in response to elevated intrahepatic bile acids, promoting spontaneous hepatocarcinogenesis by stimulating progression from NAFLD to NASH and fibrosis.

“Among top deregulated gene pathways, the nuclear receptor CAR is constitutively activated by a combination of overexpression, in response to SNS dysfunction and peripheral clock disruption, and transactivation, in response to elevated intrahepatic bile acids, to promote spontaneous hepatocarcinogenesis by stimulating the progression from NALFD to NASH and fibrosis (Figure 7I).”

May combine two claims.

Sympathetic dysfunction and peripheral clock disruption have been linked to oncogenic activation and increased risk of cancer.

“both of which have been linked to oncogenic activation and increased risk of cancer (Kettner NM, 2016; Lee et al., 2010; Magnon et al., 2013).”

• cites Kettner NM, 2016Not checked yet

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• cites Lee et al., 2010 sourceNot checked yet

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• cites Magnon et al., 2013 sourceNot checked yet

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May combine two claims.

Chronic circadian disruption induces neuroendocrine dysfunction, leading to coupled peripheral clock disruption, genome-wide gene deregulation, oncogenic activation, and global metabolic dysfunction in the liver.

“We propose that chronic circadian disruption induces neuroendocrine dysfunction, leading to a coupled peripheral clock disruption, genome-wide gene deregulation, oncogenic activation and global metabolic dysfunction in the liver.”