mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis
Open accessAbstract
SUMMARY The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.
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Written from the paper’s full text.
TL;DR
Rapamycin-mediated mTOR inhibition protects normal oral epithelial stem cells from radiation- and replicative-senescence–induced depletion, largely by increasing MnSOD and reducing ROS/oxidative stress. In mice, this preserves the proliferative basal epithelial compartment and prevents radiation-induced mucositis without substantially sensitizing HNSCC cells to radiation.
Key findings
- Rapamycin increased colony size and colony-forming efficiency of control and irradiated primary human oral keratinocytes (NOK), while only slightly sensitizing HN12 and Cal27 HNSCC cells to radiation-induced death.
- Rapamycin reduced senescence in NOK: lower γH2AX, p16, and SA-β-gal; p16 knockdown increased colony-forming efficiency. Continuous rapamycin almost tripled lifespan and cumulative population doublings, with an estimated increase from ~10^6 cells per single cell in controls to ~10^17 cells with rapamycin.
- The protective effect correlated with increased MnSOD protein in NOK but not HN12 cells; MnSOD knockdown increased basal p16 and γH2AX and abrogated rapamycin’s increase in clonogenic capacity. Rapamycin did not increase MnSOD mRNA but increased total and acetylated MnSOD.
- In C3H mice given fractionated radiation (6 Gy/day for 5 days) with rapamycin (5 mg/kg), mucositis/ulcers were almost completely prevented; vehicle-treated mice showed ulceration up to 50% of the tongue surface. Rapamycin preserved p63, cytokeratin 5, and Ki-67 in basal epithelial cells, but did not protect against a single high-dose 15 Gy.
Methods
- In vitro: primary human NOK isolated from gingival biopsies of healthy volunteers (passages 2–4) and HNSCC lines HN12 and Cal27; assays included clonogenic survival, irradiation, immunoblot, Luminex cytokine measurements, EdU proliferation, TUNEL apoptosis, SA-β-gal senescence, DHE ROS measurement, immunofluorescence, and MnSOD knockdown.
- In vivo: female C3H mice, head/neck irradiation with fractionated 6 Gy/day for 5 days and intraperitoneal rapamycin (5 mg/kg) before each dose; tongues analyzed by histology/immunofluorescence for p53, γH2AX, MnSOD, p63, cytokeratin 5, and Ki-67. Results correspond to 6 animals and are representative of 3 independent experiments.
- Main analyses: surviving fraction, colony counts/size via ImageJ, colony-forming efficiency, population doublings, cytokine levels normalized to protein, and quantification of positive cells by microscopy/FACS.
Limitations
- Stated: the precise mechanism by which mTOR blockade increases MnSOD protein expression is not known; rapamycin did not increase MnSOD mRNA, suggesting translational or posttranslational/stability effects that warrant further investigation.
- Stated: rapamycin did not protect from mucositis when mice received high-intensity single-dose radiation (15 Gy), indicating protection may be limited to clinically relevant fractionated doses.
- Evident from the text: the findings rely on primary human cell cultures and a mouse mucositis model, with no human clinical data; HNSCC radiosensitization by rapamycin was only limited in vitro.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 57 cited sources checked · 0 supported · 0 flagged
- Findingown data
mTOR inhibition with rapamycin only subtly increases the cytotoxic effect of ionizing radiation in a panel of HNSCC-derived cell lines.
“We observed only a subtle increase in the cytotoxic effect of ionizing radiation in a panel of HNSCC-derived cells lines.”
- Also stated in: § mTOR inhibition protects primary human keratinocytes from loss of clonogenic capacity · plain
“we detected only a limited synergistic effect on radiation-induced cell death in vitro, as judged by the surviving fraction of cells exposed to clinically-relevant, sub-lethal doses of radiation in the presence of rapamycin”
Quote in the paperSubstantial claim- Rests on an assumption: The sub-lethal radiation doses used in vitro are clinically relevant.
- Also stated in: § mTOR inhibition protects primary human keratinocytes from loss of clonogenic capacity · plain
- Findingown data
mTOR inhibition protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo.
“mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo”
Quote in the paperSubstantial claim - Findingown data
Rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells.
“Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence.”
Quote in the paperSubstantial claim - Findingown data
mTOR inhibition protects normal oral epithelial cells from ionizing radiation-induced epithelial stem cell depletion.
“we found that mTOR inhibition protects normal oral epithelial cells from ionizing radiation-induced epithelial stem cell depletion.”
Quote in the paperSubstantial claim - Findingown data
Rapamycin treated NOK exposed to radiation show reduced levels of γH2AX at early and late time points.
“we found that rapamycin treated NOK exposed to radiation show reduced levels of the DNA damage response marker γH2AX at early and late time points (Figures 2C and 2D).”
Quote in the paperSubstantial claim
- Findingown data
Rapamycin did not affect phosphorylation levels of Akt after treatment in NOK despite complete mTOR inhibition.
“while mTOR activity was completely inhibited by rapamycin in these cells, we did not observe any effect on the phosphorylation levels of Akt after rapamycin treatment (Figures 1C and 1F).”
Quote in the paperSubstantial claim - Findingown data
Rapamycin increased colony forming efficiency of control and irradiated human NOK.
“rapamycin also increased the colony forming efficiency of control and irradiated human NOK (Figure 1E).”
Quote in the paperSubstantial claim - Findingown data
No significant difference in number of apoptotic cells by TUNEL after irradiation in control and rapamycin treated cells.
“nor in the number of apoptotic cells as judged by TdT-mediated dUTP nick end labeling (TUNEL) assays (Figure 2B)”
Quote in the paperSubstantial claim - Findingown data
No significant differences in p53 levels in NOK after radiation exposure between control and rapamycin treated cells.
“We could not observe significant differences on the levels of p53 in NOK after radiation exposure (Figure 2A)”
Quote in the paperSubstantial claim - Findingown data
Rapamycin treatment reduced only slightly proliferation of NOK as judged by EdU staining.
“rapamycin treatment reduced only slightly the proliferation of NOK as judged by labeling of individual proliferating cells by EdU staining (Figure S2).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of p16 in NOK resulted in significant increase in colony forming efficiency under control conditions and after ionizing radiation.
“knockdown of p16 in NOK (Figure 2H, insert) resulted in a significant increase in the colony forming efficiency of NOK under control conditions as well as after ionizing radiation (Figure 2H).”
Quote in the paperSubstantial claim - Findingown data
Rapamycin-treated NOK after radiation show reduced levels of p16.
“we observed reduced levels of the senescence marker p16 in rapamycin-treated NOK after radiation (Figure 2E and 2F)”
Quote in the paperSubstantial claim - Findingown data
Rapamycin treatment did not affect expression of catalase or cytosolic superoxide dismutase (Cu-ZnSOD).
“rapamycin treatment did not affect the expression of catalase or cytosolic superoxide dismutase (Cu-ZnSOD)”
Quote in the paperSubstantial claim - Findingown data
Five days of radiation did not result in increase in mTOR activity in vehicle-treated animals as judged by phosphorylation of S6.
“Five days of radiation (day 5) did not result in an increase in mTOR activity in vehicle-treated animals as judged by phosphorylation of S6 (Figure 5B).”
Quote in the paperNot a substantial claim - Findingown data
Rapamycin treatment did not induce significant changes in ratio of reduced/oxidized glutathione (GSH).
“Rapamycin treatment did not induce significant changes in the ratio of reduced/oxidized glutathione (GSH) (Figure S3A)”
Quote in the paperSubstantial claim - Findingown data
Rapamycin did not protect from mucositis when mice were irradiated with high intensity single dose (15 Gy).
“rapamycin did not protect from mucositis when mice were irradiated with high intensity in a single dose (15 Gy, Figures S4B and S4C)”
Quote in the paperSubstantial claim - Findingown data
Decreased expression of MnSOD abrogated increased clonogenic capacity of rapamycin-treated NOK under normal conditions and after radiation.
“decreased expression of MnSOD abrogated the increased clonogenic capacity of rapamycin-treated NOK under normal conditions and after radiation (Figure 4G).”
Quote in the paperSubstantial claim - Findingown data
mTOR inactivation by rapamycin concomitant with radiation almost completely prevented appearance of mucositis/ulcers in irradiated mice.
“mTOR inactivation by rapamycin concomitant with radiation almost completely prevented the appearance of mucositis/ulcers in irradiated mice (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
No substantial differences between control and rapamycin-treated mice in visible accumulation of p53 in basal epithelial cells after radiation.
“we did not observe substantial differences between control and rapamycin-treated mice in the visible accumulation of p53 in basal epithelial cells after radiation (Figure 6A).”
Quote in the paperNot a substantial claim - Findingown data
Pretreatment of primary NOK with rapamycin prevented appearance of γH2AX and p16 following H2O2 treatment.
“pretreatment of primary NOK with rapamycin prevented the appearance of the DNA damage marker γH2AX and the expression of the senescence marker p16 following H2O2 treatment (Figure 4B)”
Quote in the paperSubstantial claim - Findingown data
Rapamycin-treated NOK showed clear reduction in p16 levels compared to increasing p16 expression with time in control cells.
“there was a clear reduction in the levels of p16 in rapamycin-treated NOK when compared to the increasing p16 expression levels with time in control cells (Figure 3F)”
Quote in the paperSubstantial claim - Findingown data
Aberrant activation of mTOR throughout basal layer of tongue epithelium 5 days after last dose of radiation (day 10) was prevented by rapamycin treatment during radiation period.
“we could observe aberrant activation of mTOR throughout the basal layer of the tongue epithelium 5 days after the last dose of radiation (day 10), which was prevented by rapamycin treatment during the radiation period (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
The effect of MnSOD knockdown on p16 and DNA damage could only be partially rescued by rapamycin.
“and this effect could only be partially rescued by rapamycin (Figure 4F).”
Quote in the paperSubstantial claim - Findingown data
Rapamycin did not prevent increase in DNA damage in HNSCC cells following H2O2 treatment.
“while it did not prevent the increase in DNA damage in HNSCC cells (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
Rapamycin significantly reduced secretion of most senescence-associated cytokines.
“rapamycin significantly reduced the secretion of most senescence-associated cytokines”
Quote in the paperSubstantial claim - Findingown data
Rapamycin treated cells almost tripled their lifespan and total cumulative population doublings compared to control cells.
“rapamycin treated cells almost tripled their lifespan and total cumulative population doublings when compared to control cells (Figures 3B, 3C and 3D).”
Quote in the paperSubstantial claim - Findingown data
Rapamycin treated cells show slightly reduced levels of differentiation marker involucrin.
“also observed that rapamycin treated cells show slightly reduced levels of the differentiation marker involucrin (Figure 2E).”
Quote in the paperNot a substantial claim - Findingown data
Continuous treatment of human primary NOK with rapamycin extended dramatically the lifespan of the cells in culture.
“continuous treatment of human primary NOK with rapamycin extended dramatically the lifespan of the cells in culture (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
No differences were observed in response to rapamycin in non-irradiated mice.
“No differences were observed in response to rapamycin innon-irradiated mice (Figure S4A).”
Quote in the paperNot a substantial claim - Findingown data
Rapamycin treatment reduced accumulation of senescent cells (SA-βgal positive) in both control and radiated cells.
“rapamycin treatment reduced the accumulation of senescent cells in both control and radiated cells (Figure 2G).”
Quote in the paperSubstantial claim - Findingcitation
In control animals, mTOR activity is restricted to the upper, more differentiated and non-proliferative layers of the oral mucosa.
“In control animals, mTOR activity is restricted to the upper, more differentiated and non-proliferative layers of the oral mucosa (Figure 5B)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Squarize et al., 2010 source
Not checked in the free run.
- Findingcitation
Rapamycin prevented radiation-induced disappearance of epithelial progenitor marker p63 and basal cell marker cytokeratin 5.
“we found that rapamycin prevented the radiation-induced disappearance of the epithelial progenitor marker p63 and the basal cell marker cytokeratin 5 (Blanpain and Fuchs, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Blanpain and Fuchs, 2009 source
Not checked in the free run.
- Findingown data
mTOR inhibition did not increase mRNA levels of MnSOD.
“mTOR inhibition did not increase the mRNA levels of MnSOD (Figure S3B)”
Quote in the paperSubstantial claim - Findingown data
Rapamycin specifically increased protein levels of MnSOD in NOK but not in HN12 cells.
“but specifically increased the protein levels of MnSOD, the mitochondrial-localized superoxide dismutase, in NOK but not in HN12 cells (Figure 4D and 4E).”
Quote in the paperSubstantial claim - Findingown data
Massive increase in SA-βgal in control cells but not in rapamycin treated cells.
“concomitant with a massive increase in SA-βgal in control cells but not in rapamycin treated cells (Figure 3G).”
Quote in the paperSubstantial claim - Findingown data
Rapamycin prevented disappearance of epithelial progenitor marker p63 in NOK cultures.
“we observed that rapamycin prevented the disappearance of the epithelial progenitor marker p63”
Quote in the paperSubstantial claim - Findingown data
Rapamycin prevented the radiation-induced block in proliferation of the basal progenitor layer of the oral epithelia at the end of the radiation regime.
“we found that rapamycin prevented also the radiation-induced block in proliferation of the basal progenitor layer of the oral epithelia at the end of the radiation regime”
Quote in the paperSubstantial claim - Findingown data
Rapamycin preserved the proliferative and tissue repopulating function of basal epithelial cells 5 days after the last radiation dose.
“preserved the proliferative and tissue repopulating function of the basal epithelial cells 5 days after the last radiation dose (Figure 6B)”
Quote in the paperSubstantial claim - Findingown data
In non-irradiated mice, rapamycin did not affect the number and distribution pattern of p63 positive cells.
“Rapamycin treatment in non-irradiated mice did not affect the number and distribution pattern of p63 positive cells (not shown)”
Quote in the paperNot a substantial claim - Findingown data
Rapamycin treatment did not increase mRNA levels of MnSOD.
“Rapamycin treatment did not increase mRNA levels of MnSOD”
Quote in the paperSubstantial claim - Findingown data
mTOR inhibition causes a remarkable reduction in ROS accumulation in irradiated NOK and in NOK undergoing replicative senescence.
“Our results show that mTOR inhibition causes a remarkable reduction in ROS accumulation in irradiated NOK as well as in NOK undergoing replicative senescence”
Quote in the paperSubstantial claim - Findingown data
MnSOD knockdown reverted the decrease in p16 expression and the protective effects of rapamycin in NOK clonogenic capacity under basal conditions and after radiation exposure.
“MnSOD knock down reverted the decrease in p16 expression and the protective effects of rapamycin in NOK clonogenic capacity under basal conditions and after radiation exposure”
Quote in the paperSubstantial claim - Findingown data
Rapamycin decreased the release of multiple senescence-associated cytokines.
“rapamycin decreased the release of multiple senescence-associated cytokines”
Quote in the paperSubstantial claim - Findingown data
mTOR inhibition decreases epithelial stem cell depletion.
“Here, we show that mTOR inhibition decreases epithelial stem cell depletion.”
Quote in the paperSubstantial claim - Findingnone given
Rapamycin is unable to increase MnSOD in HNSCC cells.
“the inability of rapamycin to increase MnSOD in these cells”
Quote in the paperSubstantial claim - Findingown data
ROS inhibition by rapamycin correlated with increased levels of MnSOD.
“Here, we observed that ROS inhibition by rapamycin correlated with increased levels of MnSOD.”
Quote in the paperSubstantial claim - Findingreasoning
Rapamycin does not increase the viability or survival of HNSCC cells.
“rapamycin does not increase the viability or survival of HNSCC cells”
Quote in the paperSubstantial claim - Premisecitation
Increased mTOR activity can cause certain cells to undergo differentiation or senescence, thereby exiting the proliferative cell pool.
“increased mTOR activity can also cause certain cells to undergo differentiation or senescence, thereby exiting the proliferative cell pool (Castilho et al., 2009; Chen et al., 2008; Lee et al., 2010; Liu et al., 2007; Zhang et al., 2006; reviewed in Iglesias-Bartolome and Gutkind, 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
The protective effect of rapamycin is mediated by increased expression of MnSOD and consequent inhibition of ROS formation and oxidative stress.
“This protective effect of rapamycin is mediated by the increase expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress.”
Quote in the paperSubstantial claim - Interpretationown data
The increase in clonogenic capacity of primary human oral keratinocytes by rapamycin is mediated by preventing stem cell senescence.
“Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence.”
Quote in the paperSubstantial claim - Interpretationown data
Increased proliferative capacity of radiated NOK upon rapamycin exposure is unlikely related to elevated Akt activity.
“This suggests that the increased proliferative capacity of radiated NOK cells upon rapamycin exposure is unlikely related to an elevated Akt activity, and hence to its pro-survival and growth promoting functions (Manning and Cantley, 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Manning and Cantley, 2007 source
Not checked in the free run.
- Interpretationown data
Differences in basal cell proliferation may contribute to, but are unlikely to account for, increased clonogenic capacity of NOK after radiation upon rapamycin treatment.
“Thus, the differences in basal cell proliferation may contribute to, but are unlikely to account for the increased clonogenic capacity of NOK after radiation upon rapamycin treatment.”
Quote in the paperSubstantial claim - Interpretationown data
Rapamycin treatment may reduce the extent of DNA damage in NOK.
“This suggests that rapamycin treatment may reduce the extent of DNA damage in NOK (Bonner et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bonner et al., 2008 source
Not checked in the free run.
- Interpretationown data
The effect of rapamycin on NOK lifespan was mediated by continuous inhibition of mTOR, as cells quickly undergo replicative senescence after rapamycin removal.
“This effect was mediated by the continuous inhibition of mTOR, as cells quickly undergo replicative senescence after rapamycin removal (Figure 3E).”
Quote in the paperSubstantial claim - Interpretationown data
mTOR inhibition reduces depletion of stem cells from NOK culture.
“indicating that mTOR inhibition reduces the depletion of stem cells from the culture.”
Quote in the paperSubstantial claim - Interpretationown data
Translational or posttranslational mechanisms rather than transcriptional events may account for increased MnSOD protein expression caused by rapamycin in NOK.
“indicating that translational or postranslational mechanisms rather than transcriptional events may account for the increased MnSOD protein expression caused by rapamycin in NOK.”
Quote in the paperSubstantial claim - Interpretationown data
Protection conferred by rapamycin treatment might only be effective at clinically-relevant fractionated radiation doses.
“indicating that the protection conferred by rapamycin treatment might only be effective at clinically-relevant fractionated radiation doses.”
Quote in the paperSubstantial claim- Rests on an assumption: The fractionated radiation regimen used in mice (6 Gy/day for 5 days) is clinically relevant.
- Interpretationreasoning
mTOR inhibition may increase clonal proliferative capacity of oral epithelial stem cells by preventing activation of specific cell senescence mechanisms.
“Together, these findings suggest that mTOR inhibition may increase the clonal proliferative capacity of oral epithelial stem cells by preventing the activation of specific cell senescence mechanisms.”
Quote in the paperSubstantial claim - Premisecitation
p63 is an epithelial stem cell marker.
“the epithelial stem cell marker p63 (Blanpain and Fuchs, 2009)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Blanpain and Fuchs, 2009 source
Not checked in the free run.
- Premisecitation
Senescent cells acquire the ability to secrete SASP cytokines, which promote growth arrest and senescence in neighboring cells.
“Senescent cells acquire the ability to secrete a variety of cytokines, often referred to as the senescence-associated secretory phenotype (SASP). These secreted cytokines have a myriad of effects on neighboring cells, including the promotion of growth arrest and senescence (Acosta et al., 2008; Coppé et al., 2008; Rodier and Campisi, 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Prevention of the loss of proliferative capacity protects from epithelial stem cell depletion and the consequent appearance of widespread ulcers and mucositis.
“which in turn, protects from epithelial stem cell depletion and the consequent appearance of widespread ulcers and mucositis”
Quote in the paperSubstantial claim - Premisecitation
Each large colony is expected to grow from a single surviving self-renewing epithelial stem cell.
“Since each large colony is expected to grow from a single surviving self-renewing epithelial stem cell (Jensen et al., 2010)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jensen et al., 2010 source
Not checked in the free run.
- Interpretationown data
Rapamycin treatment prevents the loss of proliferative capacity of the epithelial progenitor and stem cell compartment after radiation.
“our observations indicate that rapamycin treatment prevents the loss of proliferative capacity of the epithelial progenitor and stem cell compartment after radiation”
Quote in the paperSubstantial claim - Interpretationown data
Inhibition of ROS formation may represent one mechanism by which rapamycin protects from cell senescence and stem cell depletion.
“thus suggesting that inhibition of ROS formation may represent one the of mechanisms by which rapamycin protects from cell senescence and stem cell depletion”
Quote in the paperSubstantial claim - Interpretationown data
mTOR inhibition might ameliorate mucositis by preventing the release of a pro-senescent and pro-inflammatory secretome from normal and irradiated cells.
“suggesting that mTOR inhibition might also ameliorative mucositis by preventing the release of a pro-senescent and pro-inflammatory secretome from normal and irradiated cells (Sonis, 2009)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sonis, 2009 source
Not checked in the free run.
- Interpretationreasoning
Signaling pathways and stress responses are often differentially wired in normal and cancer cells.
“which highlights the fact that signaling pathways and stress responses are often differentially wired in normal and cancer cells”
Quote in the paperSubstantial claim - Premisecitation
Generation of ROS is an important mediator of cellular alterations caused by radiation exposure, including mucositis.
“The generation of ROS is also an important mediator of the cellular alterations caused by radiation exposure (Diehn et al., 2009; Sonis, 2009; Spitz et al., 2004), including mucositis (Citrin et al., 2010; Cotrim et al., 2007; Cotrim et al., 2005).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Increased MnSOD mediates the beneficial effects of mTOR inhibition in primary human NOK.
“we obtained evidence that increase MnSOD mediates the beneficial effects of mTOR inhibition in primary human NOK”
Quote in the paperSubstantial claim - Premisecitation
Persistent activation of mTOR by Wnt1 leads to accelerated epithelial stem cell senescence and premature aging in mice.
“we have recently shown that the persistent activation of mTOR by Wnt1 leads to accelerated epithelial stem cell senescence and premature aging in mice (Castilho et al., 2009; Liu et al., 2007)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Increased mTOR activity can cause cells to undergo differentiation or senescence, thereby exiting the proliferative cell pool.
“increased mTOR activity paradoxically can also cause cells to undergo differentiation or senescence, thereby exiting the proliferative cell pool (reviewed in Iglesias-Bartolome and Gutkind, 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Iglesias-Bartolome and Gutkind, 2011
Not checked in the free run.
- Interpretationreasoning
The protective effect of mTOR inhibition involved increased expression of MnSOD in the basal progenitor epithelial cell layer.
“this protective effect of mTOR inhibition involved increased expression of MnSOD in the basal progenitor epithelial cell layer”
Quote in the paperSubstantial claim - Interpretationown data
Aberrant activation of the mTOR pathway plays a predominant role mediating the depletion of the epithelial stem cell compartment.
“demonstrate that the aberrant activation of the mTOR pathway plays a predominant role mediating the depletion of the epithelial stem cell compartment”
Quote in the paperSubstantial claim - Interpretationreasoning
This explains why rapamycin exposure does not have any impact on the activation of p16-dependent cell senescence pathways in HNSCC.
“This could in turn help explain why rapamycin exposure does not have any impact on the activation of p16-dependent cell senescence pathways in HNSCC.”
Quote in the paperNot a substantial claim - Premisecitation
In the oral mucosa, loss of proliferative and repopulating activity of normal epithelial stem cells, in conjunction with other factors, can lead to mucositis, characterized by disruption of epithelial integrity, ulceration and pain.
“In the oral mucosa, this process, in conjunction with other factors, can lead to mucositis, a mucosal injury characterized by disruption of epithelial integrity, ulceration and pain (Sonis, 2009, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sonis, 2009, 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Mitochondrial oxidative damage contributes to mTOR-dependent cellular senescence in adult tissue-regenerating cells.
“our results support the likely contribution of mitochondrial oxidative damage to mTOR-dependent cellular senescence in adult tissue-regenerating cells”
Quote in the paperSubstantial claim
- May combine two claims. 30
- Classified as probably not a substantial claim. 20
May combine two claims.
Findingown dataInhibition of mTOR prevents the loss of proliferative epithelial progenitor stem cells upon radiation and enhances their tissue repopulating capacity, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.
“We found that inhibition of mTOR prevents the loss of proliferative epithelial progenitor stem cells upon radiation and enhances their tissue repopulating capacity, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRapamycin protects epithelial progenitor cells from replicative senescence, extending dramatically their life span in vitro.
“rapamycin also protected epithelial progenitor cells from replicative senescence, extending dramatically their life span in vitro.”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningmTOR inhibition preserves the integrity of the oral mucosa and protects from radiation-induced mucositis.
“thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRapamycin does not significantly affect the size of colonies growing after radiation in HNSCC cells, while completely inhibiting mTOR activity as assessed by phosphorylation of S6.
“The size of the colonies growing after radiation was also not significantly affected by rapamycin, which completely inhibited mTOR activity as assessed by the phosphorylation of S6 (Figures 1A and 1B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRapamycin significantly enhanced colony size of NOK compared with vehicle treated cells, and this increase was maintained after radiation.
“rapamycin significantly enhanced the colony size of NOK compared with vehicle treated cells, and this increase was maintained after radiation (Figures 1C and 1D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMnSOD knockdown in NOK increased basal levels of p16 expression and DNA damage as measured by γH2AX.
“MnSOD knockdown in NOK increased the basal levels of p16 expression and DNA damage as measured by γH2AX”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRapamycin prevented the remarkable increase in ROS preceding NOK cell growth arrest (10 days) and in cells undergoing replicative senescence (40 days).
“rapamycin prevented the remarkable increase in ROS preceding NOK cell growth arrest (Figure 4A, 10 days) as well as in cells undergoing replicative senescence (Figure 4A, 40 days).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth total and acetylated MnSOD increased upon rapamycin treatment in human NOK.
“both total and acetylated MnSOD increased upon rapamycin treatment in human NOK (Figure S3C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHistological analysis revealed preservation of epithelial layer in irradiated rapamycin-treated mice, although radiation-associated tissue changes were observed.
“Histological analysis of the tongues revealed the preservation of the epithelial layer in irradiated rapamycin-treated mice, although radiation-associated tissue changes were observed (Figure 5D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRapamycin treatment did not increase expression, nuclear localization, or transcriptional activation of FoxO proteins, nor changes in expression of SIRT family members.
“we did not observe an increase in the expression, nuclear localization, or transcriptional activation of FoxO proteins, nor changes in the expression of SIRT family members”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRapamycin-treated mice after radiation showed remarkable reduction in levels of γH2AX and increased levels of MnSOD.
“we observed a remarkable reduction in the levels of γH2AX and increased levels of MnSOD (Figure 6A)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRapamycin treatment prevented induction of ROS after radiation in primary NOK, while it failed to protect from ROS accumulation in HNSCC cells.
“we found that rapamycin treatment prevented the induction of ROS after radiation in primary NOK, while it failed to protect from ROS accumulation in HNSCC cells (Figure 4A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExtensive ulceration, up to 50% of surface of tongue, was evident in vehicle-treated animals, which was absent in all rapamycin treated mice.
“extensive ulceration, up to 50% of the surface of the tongue, was evident in the animals treated with vehicle, which was absent in all rapamycin treated mice (Figure 5D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn absence of rapamycin a single cell gives rise approximately to 10^6 cells before senescence; in presence of rapamycin around 10^17 cells.
“We can estimate that while in the absence of rapamycin a single cell will give rise approximately to 106 cells before undergoing senescence, while in the presence of rapamycin a single cell will give rise to around 1017 cells.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataRapamycin caused a slight but significant increase in p63 expression levels in basal progenitor cells.
“we only observed a slight and yet significant increase in the levels of p63 expression in basal progenitor cells upon rapamycin treatment (Figure S5)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRapamycin treatment on mice was effective at limiting the loss of proliferative basal oral epithelial stem cells upon radiation, enhancing their tissue repopulating capacity and preventing the appearance of ulcers.
“Rapamycin treatment on mice was effective at limiting the loss of proliferative basal oral epithelial stem cells upon radiation, thereby enhancing their tissue repopulating capacity and preventing the appearance of ulcers.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamTOR inhibition by rapamycin prevented the appearance of DNA damage and the expression of the senescence marker p16 after direct exposure of human primary NOK to hydrogen peroxide-induced oxidative stress.
“mTOR inhibition by rapamycin prevented the appearance of DNA damage and the expression of the senescence marker p16 after the direct exposure of human primary NOK to hydrogen peroxide-induced oxidative stress”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRapamycin promotes an increase in both total and acetylated form of MnSOD.
“We observed that rapamycin promotes an increase in both total and acetylated form of MnSOD”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmTOR activation is one of the most frequent events in human malignancies arising from the epithelial cells lining the oral mucosa, tongue and pharynx (HNSCC).
“mTOR activation is one of the most frequent events in human malignancies arising from the epithelial cells lining the oral mucosa, tongue and pharynx, collectively referred to as head and neck squamous cell carcinomas (HNSCC) (Molinolo et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Molinolo et al., 2007 source
Not checked in the free run.
May combine two claims.
InterpretationcitationThe protective effect of mTOR inhibition is mediated by increased expression of MnSOD and consequent suppression of oxidative stress caused by ROS accumulation in normal but not cancer cells.
“Emerging evidence suggest that this protective effect of mTOR inhibition is mediated by the increased expression of mitochondrial superoxide dismutase (MnSOD), and the consequent suppression of oxidative stress caused by the accumulation of reactive oxygen species (ROS) in normal but not in cancer cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInhibition of mTOR by rapamycin and its derivatives has shown promising antitumoral activity in a variety of experimental models of HNSCC.
“Inhibition of mTOR by the use of rapamycin and its derivatives has shown promising antitumoral activity in a variety of experimental models of HNSCC (Amornphimoltham et al., 2008; Amornphimoltham et al., 2005; Czerninski et al., 2009; Nathan et al., 2007)”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningRapamycin increases survival and repopulating capacity of epithelial progenitors, protecting from radiation-induced loss of this tissue regenerative cell population.
“these findings indicate that rapamycin increases the survival and repopulating capacity of epithelial progenitors, hence protecting from radiation-induced loss of this tissue regenerative cell population.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jensen et al., 2010 source
Not checked in the free run.
May combine two claims.
PremisecitationROS can mediate the deleterious effects of radiation and contribute to DNA damage and activation of senescence pathways in cells.
“reactive oxygen species (ROS) can mediate the deleterious effects of radiation and contribute to DNA damage and the activation of senescence pathways in cells (Diehn et al., 2009; Kuilman et al., 2010; Sonis, 2009; Spitz et al., 2004).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMnSOD activity and stability are highly regulated by post-translational modifications, including protein acetylation in mitochondria.
“MnSOD activity and stability are highly regulated by post-translational modifications, including protein acetylation in the mitochondria (Takahashi et al., 2011; Tao et al., 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationActivation of the DNA damage response is one of the main mediators of cell senescence, resulting in irreversible growth arrest.
“The activation of the DNA damage response is one of the main mediators of cell senescence, which results in irreversible growth arrest (Kuilman et al., 2010; Rodier and Campisi, 2011).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCytokeratin 5 is a basal cell marker.
“the basal cell marker cytokeratin 5 (Blanpain and Fuchs, 2009)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Blanpain and Fuchs, 2009 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationmTOR inhibitors can sensitize other tumor types to radiation.
“Given that mTOR inhibitors can sensitize other tumor types to radiation (Eshleman et al., 2002; Konstantinidou et al., 2009; Murphy et al., 2009)”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMnSOD has been linked to radiation resistance, and its deficiency can promote appearance of accelerated aging phenotypes.
“MnSOD has been linked to radiation resistance, and its deficiency can promote the appearance of accelerated aging phenotypes (Hosoki et al., 2012; Velarde et al., 2012; Weyemi et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationActivation of the RB tumor suppressive pathway by accumulation of p16 is often considered a key mechanism triggering cell senescence in several systems, including skin keratinocytes.
“The activation of the RB tumor suppressive pathway by the accumulation of p16 is often considered a key mechanism triggering cell senescence in several systems, including skin keratinocytes (Kuilman et al., 2010; Luis et al., 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrimary human NOK isolated by similar procedures include cells with long-term self-renewal capacity, as judged by their ability to support prolonged survival of corneal implants in humans.
“Simple procedures are currently available to isolate primary human NOK that include cells with long-term self-renewal capacity, as judged by their ability to support the prolonged survival of corneal implants in humans (Chen et al., 2009; Nakamura et al., 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Chen et al., 2009
Not checked in the free run.
- cites Nakamura et al., 2007
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSA-βgal is a known marker of senescent cells.
“senescence-associated beta-galactosidase (SA-βgal), a known marker of senescent cells (Debacq-Chainiaux et al., 2009)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Debacq-Chainiaux et al., 2009 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA reduction in ROS formation after mTOR blockade has been documented in drosophila cells and human T cells.
“a reduction in ROS formation after mTOR blockade has been documented in drosophila cells and human T cells, albeit by a yet to be determined molecular mechanism (Lee et al., 2010; Schieke et al., 2006)”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
PremisecitationMnSOD is the main ROS scavenger in the inner mitochondrial matrix and acts as the first line of defense against mitochondrial oxidative damage.
“MnSOD is the main ROS scavenger in the inner mitochondrial matrix, and acts as the first line of defense against mitochondrial oxidative damage (Holley et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Holley et al., 2011 source
Not checked in the free run.
May combine two claims.
Interpretationown dataRapamycin prevents cells from entering senescence and terminal differentiation programs during replicative senescence or radiation-induced stress conditions, without protecting HNSCC cells from radiation-induced cell death.
“Our results indicate that rapamycin prevents cells from entering senescence and terminal differentiation programs during replicative senescence or when exposed to radiation-induced stress conditions, without protecting HNSCC cells from radiation-induced cell death.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTargeted deletion of MnSOD in connective tissue results in reduced lifespan that correlates with an increase in cell senescence due to p16 expression.
“its targeted deletion in connective tissue results in reduced lifespan that correlates with an increase in cell senescence due to the expression of p16 (Treiber et al., 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Treiber et al., 2011 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataEnhanced MnSOD protein expression may result from increased translation or posttranslational events such as enhanced protein stability.
“indicating that its enhanced protein expression may result from increased translation or yet to be identified postranslational events, such as enhanced protein stability”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSenescence can be triggered by multiple mechanisms, including ROS production and oxidative stress.
“Senescence can be triggered by multiple mechanisms, including those resulting in ROS production and oxidative stress (Kuilman et al., 2010; Rodier and Campisi, 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataRapamycin may affect the stability of MnSOD through changes in acetylation of the enzyme.
“indicating that rapamycin may affect the stability of MnSOD through changes in acetylation of the enzyme”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningBy increasing the expression of MnSOD, mTOR inhibitors may reduce ROS-induced DNA damage, oxidative stress, and ultimately epithelial stem cell senescence, protecting from radiation-induced depletion of tissue-repopulating stem cells and the concomitant appearance of ulcers and mucositis.
“these results raise the possibility that by increasing the expression of MnSOD, mTOR inhibitors may reduce ROS-induced DNA damage, oxidative stress, and ultimately epithelial stem cell senescence, protecting from radiation-induced depletion of tissue-repopulating stem cells and the concomitant appearance of ulcers and mucositis (Figure S6)”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMitochondrial oxidative stress resulting from MnSOD deficiency results in cellular senescence in mouse skin, associated with increased nuclear DNA damage.
“mitochondrial oxidative stress resulting from MnSOD deficiency results in cellular senescence in mouse skin, a process associated with increased nuclear DNA damage (Velarde et al., 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Velarde et al., 2012 source
Not checked in the free run.
May combine two claims.
PremisecitationHNSCC arises from multiple genetic and epigenetic alterations, and loss of heterozygosity in the p16 locus with inability to express the remaining allele due to p16 promoter methylation is one of the earliest events in HNSCC progression.
“HNSCC arises from multiple genetic and epigenetic alterations, and among them, loss of heterozygosity in the p16 locus concomitant with the inability to express the remaining allele due to p16 promoter methylation is one of the earliest events in HNSCC progression (Rosas et al., 2001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rosas et al., 2001
Not checked in the free run.
Classified as probably not a substantial claim.
Interpretationnone givenThe demise of stem cells by senescence or differentiation in response to extrinsic or intrinsic cellular stress pathways may represent a key mechanism driving stem cell depletion, thereby contributing to reduced tissue regenerative capacity.
“The demise of stem cells by senescence or differentiation in response to extrinsic or intrinsic cellular stress pathways may represent a key mechanism driving stem cell depletion, thereby contributing to reduced tissue regenerative capacity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationcitationInterventional strategies reducing the deleterious effect of radiation on normal epithelia and preserving the integrity of the oral mucosa will have a great impact on the quality of life of cancer patients.
“interventional strategies reducing the deleterious effect of radiation on normal epithelia and hence preserving the integrity of the oral mucosa will have a great impact in the quality of life of cancer patients (Citrin et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Citrin et al., 2010 source
Not checked in the free run.
- Rests on an assumption: Loss of proliferative and repopulating activity of normal epithelial stem cells is an undesired secondary effect of most antineoplastic treatments.
May combine two claims.
InterpretationcitationmTOR inhibition with rapamycin and newly developed agents may prevent the appearance of radiation-induced mucositis and its consequent negative impact on anticancer treatment outcome and cost.
“our findings indicate that by preserving the tissue repopulating capacity of the epithelial stem cells, mTOR inhibition with rapamycin and newly developed agents (Wander et al., 2011) may prevent the appearance of radiation-induced mucositis and its consequent negative impact on anticancer treatment outcome and cost”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wander et al., 2011 source
Not checked in the free run.
- Rests on an assumption: Loss of proliferative and repopulating activity of normal epithelial stem cells is an undesired secondary effect of most antineoplastic treatments.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRadiotherapy is one of the most widely used antineoplastic treatments, including almost 80% of patients with head and neck cancer.
“As radiotherapy is one of the most widely used antineoplastic treatments, including almost 80% of patients with head and neck cancer (Delaney et al., 2005)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Delaney et al., 2005 source
Not checked in the free run.
May combine two claims.
PremisecitationThe E6 HPV oncogene promotes p53 degradation, and the E7 HPV oncogene binds and inhibits RB, rendering p16 unable to stimulate its tumor suppressive functions.
“While the E6 HPV oncogene promotes p53 degradation, the HPV E7 oncogene binds and inhibits RB, thereby rendering p16 unable to stimulate its tumor suppressive functions (Moody and Laimins, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Moody and Laimins, 2010
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApproximately 20% of all HNSCC cases are associated with HPV16 infection.
“Approximately 20% of all HNSCC cases are also now known to be associated with HPV16 infection (zur Hausen, 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites zur Hausen, 2009 source
Not checked in the free run.
May combine two claims.
Interpretationreasoningp16 inactivation by genetic and epigenetic events or by viral oncogenes is a shared feature in most HNSCC lesions, rendering mTOR inhibitors unable to affect p16 expression or function in these cells.
“Thus, p16 inactivation by genetic and epigenetic events or by viral oncogenes is a shared feature in most HNSCC lesions, which therefore renders mTOR inhibitors unable to affect p16 expression or function in these cells.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The fractionated radiation regimen used in mice (6 Gy/day for 5 days) is clinically relevant.
“fractionated radiation of a 6 grays (Gy) dose/day/mouse for 5 days”
“clinically-relevant fractionated radiation doses”
The paper relies on this without support.
The sub-lethal radiation doses used in vitro are clinically relevant.
“clinically-relevant, sub-lethal doses of radiation”
The paper relies on this without support.
Loss of proliferative and repopulating activity of normal epithelial stem cells is an undesired secondary effect of most antineoplastic treatments.
“loss of proliferative and repopulating activity of normal epithelial stem cells is an undesired secondary effect of most antineoplastic treatments”
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?
Rapamycin inhibits cell senescence in vitro.
“Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species.”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Iglesias‐Bartolome et al., 2012
The citation lists haven’t been fetched yet
References 62 · Cited by 284
- Authors
- Iglesias-Bartolome, R., Patel, V., Cotrim, A., Leelahavanichkul, K., Molinolo, A. A., Mitchell, J. B., & Gutkind, J. S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gutkind, J. Silvio
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 11
- Issue
- 3
- Pages
- 401-414
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC3477550
- OpenAlex
- W2164671411
- Semantic Scholar
- 9837adecbd45b1f030829e8de13adafa0f0d9ba9
- Cited by
- 284
- References
- 62
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 9 · 2023: 20 · 2022: 14 · 2021: 14 · 2020: 24 · 2019: 33 · 2018: 18 · 2017: 28 · 2016: 22 · 2015: 23 · 2014: 28 · 2013: 28 · 2012: 5
- FWCI
- 21.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Dental and Craniofacial Research (ZIADE000558, ZIADE000551)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Oral health in cancer treatment
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- mTOR inhibition, rapamycin, radiation-induced mucositis, oral keratinocytes, oral mucosa, mitochondrial superoxide dismutase, reactive oxygen species, oxidative stress, ionizing radiation, clonogenicity
- MeSH terms
- Animals, Carcinoma, Squamous Cell, Cell Compartmentation, Cells, Cultured, Clone Cells, Epithelial Cells, Head and Neck Neoplasms, Humans, Mouth Mucosa, Radiation Injuries, Radiation, Ionizing, Stem Cells, Superoxide Dismutase, Keratinocytes, Cellular Senescence, Cell Death, Oxidative Stress, Cytoprotection, Sirolimus, Cell Proliferation, Mice, Mucositis, TOR Serine-Threonine Kinases
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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.
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
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