"Hutchinson-Gilford Progeria Syndrome" by The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T; https://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg#/media/File:HIV-budding-Color.jpg. "HIV-budding-Color" by Photo Credit: C. Goldsmith. Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus.
Another recent post of mine (see below) from LinkedIn on a study that is definitely a HUGE plus in making my hypothesis on treating/reversing progeria that much more real. Metformin, a widely-prescribed anti-diabetic drug derived from the plant Galega officinalis (a plant that has been used to treat symptoms of diabetes mellitus dating back to the Middle Ages) that has been shown to increase the lifespan and healthspan of several organisms, corrects gene splicing in cells from patients with the autosomal-dominant muscle wasting disease myotonic dystrophy type I (DM1). Progeria is an autosomal-dominant disease like DM1 and both are characterized by faulty gene splicing. What's super interesting about this study is that metformin also beneficially altered gene splicing in human diabetic patients taking metformin who didn't have DM1. Just as methylene blue, retinoic acid (vitamin A metabolite), and sulforaphane (broccoli sprout compound) all activate AMPK and reverse aging defects in progeria cells, I think I was the first one to predict via my publications that metformin (and other AMPK activators) may correct gene splicing and reverse aging defects in progeria cells by activating AMPK. Because this study shows that metformin can do just that (alter gene splicing) in the disease DM1 and in normal diabetics and because metformin also enhances the reactivation of dormant HIV-1 infected T cells, it seems that maybe my hypothesis of disease interconnectedness may turn out to be true. IF IT DOES......................:-)
AMPK activator Metformin alters gene splicing in humans: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation
A recent study published online in the Journal Molecular Therapy Nucleic Acids in November of 2015 provided startling evidence that metformin, a widely-prescribed anti-diabetic drug derived from the plant Galega officinalis (a plant that has been used to treat symptoms of diabetes mellitus dating back to the Middle Ages) that has been shown to increase the lifespan and healthspan of several organisms, corrects alternative splicing defects in primary myoblasts derived from patients with myotonic dystrophy type I (DM1) as well as in derivatives of embryonic stem cells that carry the DM1 mutation in an AMPK-dependent manner. Strikingly, metformin also beneficially altered the splicing of the insulin receptor gene in diabetic patients who were taking metformin but who did not have DM1, in typical therapeutic dosages [1].
DM1, a genetic disorder inherited in an autosomal dominant fashion, is characterized by muscle weakness and wasting, cardiac conduction abnormalities, and myotonia (prolonged muscle contraction) [2]. According to the NIH, “ ‘Autosomal’ means that the gene in question is located on one of the numbered, or non-sex, chromosomes. ‘Dominant’ means that a single copy of the disease-associated mutation is enough to cause the disease.” [3]. DM1 is known as a trinucelotide repeat disorder, a condition in which there is an expansion or repeat of two or three nucleotides in a particular gene that can lead to manifestation of disease if the sequence of repeats extends beyond a certain number. For example, the affected gene in DM1, called DMPK, codes for a protein that is primarily expressed in skeletal muscle. A repeat expansion consisting of the cytosine-thymine-guanine (CTG) triplet between 5 and 37 repeats is considered normal while repeats exceeding 50 nearly always results in symptomatic disease [4].
Interestingly, DM1 is also known as a model of spliceopathy (i.e. misregulated alternative splicing), and is characterized by defects in the alternative RNA splicing machinery, generating alternatively spliced isoforms that contribute to the severity of the disease, including insulin resistance [1]. Using mesodermal precursor cells (MPCs) that were derived from embryonic stem cells from an embryo that was a DM1-gene carrier, the authors initially showed that metformin corrected splicing defects in the insulin receptor (INSR) gene by increasing the proportion of INSR with exon 11 inclusion in both DM1 MPCs and in wild-type MPCs, indicating that metformin has the ability to positively regulate alternative splicing in normal cells as well as in mutated cells [1]. Metformin also corrected alternative splicing defects in the DM1-associated genes TNNT2 and Cln1 by lowering the percentage of exon 5 inclusion in TNNT2 and lowering the percentage of exon 7a inclusion in Clcn1 to levels similar to wild-type MPCs [1]. Additionally, using deep RNA sequencing, the authors also demonstrated that metformin altered gene expression and alternative splicing of a large number of genes in DM1 MPCs, with metformin affecting the expression of a total of 1,171 genes and regulating eighty-nine splicing events and 416 exons above 10% [1].
Metformin’s mechanism of action has been shown to be dependent on its ability to activate the master metabolic regulator AMPK by increasing the intracellular AMP/ATP ratio, thus inducing a compensatory cellular stress response [5]. Indeed, the authors showed that metformin specifically inhibited complex I of the mitochondrial electron transport chain in DM1 MPCs, leading to an increase in the AMP/ATP ratio [1]. Additionally, by using AICAR, a pharmacological AMPK activator widely used in studies to asses the effects of AMPK activation, the authors showed that treatment of DM1 MPCs with AICAR altered exon inclusion on five of the splicing events most regulated by metformin (MDM4 exon 7 [decreased exon inclusion], GPCPD1 exon 5 [decreased exon inclusion], CCNL2 exon 7 [increased exon inclusion], RAGE exon 3 [decreased exon inclusion], and ZFAND1 exon 3 [decreased exon inclusion]) [1]. Such data provides compelling evidence that metformin alters alternative splicing via the activation of AMPK.
The authors however extended the analysis one step further, testing the effects of metformin treatment on alternative splicing events associated with muscle strength by using myoblasts from two different patients diagnosed with DM1 and two healthy patients. Interestingly, metformin beneficially altered the splicing of 6 genes (INSR exon 11, TNNT2 exon 5, ATP2A1 exon 22, DMD exon 71, DMD exon 78, and KIF13A exon 32), as evidenced by a shift in the isoform ratio towards control values [1].
Perhaps most importantly, however, was the verification of metformin’s effect on alternative splicing in vivo via the use of human subjects. A clinical trial was performed wherein 15 diabetic patients, who did not have DM1 but were currently taking metformin for more than a year (between 2.1 and 3 g/day), were recruited and the effects of metformin on alternative splicing were conducted on peripheral blood lymphocytes (PBLs). Strikingly, using quantitative PCR, the authors showed that metformin triggered the inclusion of INSR exon 11 in a clinical setting. However, when metformin was temporarily replaced by another diabetic drug that was shown in other experiments not to effect INSR exon 11 alternative splicing, INSR exon 11 inclusion was decreased. However, when the patients were placed back on metformin, INSR exon 11 inclusion increased, indicating that metformin also alters alternative splicing in vivo in human subjects. Curiously, metformin also decreased FAS (CD95) exon 6 exclusion in PBLs from treated patients, generating a shift from the anti-apoptotic to the pro-apoptotic protein isoform [1].
The results from this study represents an incredible example of how compounds as chemically distinct as metformin, retinoic acid, sulforaphane, and likely many others share a common indirect mechanism of action of AMPK activation, leading to correction of gene splicing in genetic disorders characterized by autosomal dominance (e.g. progeria and DM1), reactivation of latent viral infections to facilitate immune system eradication (e.g. HIV-1 latency), and regulation of cellular processes that are almost universally associated with both normal and accelerated aging (e.g. mitochondrial dysfunction and telomere erosion).
Indeed, methylene blue has recently been shown to reverse accelerated aging defects, correct mitochondrial function, increase PGC1a levels, and increase lamin A mRNA (evidence of alteration of alternative splicing) in fibroblasts derived from patients with Hutchinson-Gilford progeria syndrome, an accelerated aging disease caused by aberrant alternative splicing of the LMNA gene [6]. Methylene blue has also shown been shown to delay cellular senescence in lung cells via AMPK activation, decrease telomere erosion, and reactivate latent HIV-1 via photosensitization (see prior post for references). Similarly, metformin has also been shown to enhance mitochondrial function through enhancing an AMPK-mediated PGC1a upregulation, correct gene splicing in an AMPK-dependent manner in DM1, increase lifespan and healthspan in several organisms, and synergize with bryostatin to enhance the reactivation of latent HIV-1 [1,7,8]. Interestingly, bryostatin, a protein kinase C activator, was also shown to phosphorylate and activate AMPK, implying that bryostatin is an indirect AMPK activator as well [8].
This common theme of AMPK activation also extends to sulforaphane, the broccoli sprout compound that was recently found to also reverse aging defects in progeria cells [9]. Sulforaphane was shown to enhance the autophagic degradation of progerin (mutant protein) in cells derived from progeria patients, increase the proportions of lamin A (normal protein) yet decrease those of progerin in progeria cells, stimulate the immune response against cancer cells, inhibit scrapie prion protein accumulation by activating AMPK, and inhibit two epigenetic factors (EZH2 and SUV39H1) that keep HIV-1 dormant in infected T cells that are also dysregulated in progeria cells (see prior post for references). As AMPK is essential for T cell activation, metformin has been shown to enhance latent HIV-1 reactivation, increase the formation of cytotoxic memory CD8+ T cells (targets and kills viruses and cancer cells), induce autophagy by activating the AMPK-ULK1 pathway, and modulate the repressive epigenetic factors EZH2 and SUV39H1 [8,10-13].
The commonality of AMPK activation between metformin and sulforaphane also extends to retinoic acid (and/or its derivatives), a vitamin A metabolite that activates AMPK and was recently shown to reverse aging defects in progeria cells, decrease progerin mRNA in progeria cells (evidence of alteration of alternative splicing), regulate the same gene splicing factors that play a role in both HGPS and latent HIV-1 reactivation, enhance T cell activation, and act synergistically with other agents to reactivate latent HIV-1 [14, see prior post for other references]. Again, AMPK activation is likely playing a critical role in each of these processes, as AMPK activation beneficially alters alternative splicing and is essential for T cell activation and thus latent HIV-1 reactivation.
Furthermore, in the 2015 Molecular Therapy Nucleic Acids study referenced above, metformin decreased FAS (CD95) exon 6 exclusion in PBLs from treated patients, generating a shift from the anti- to the pro-apoptotic isoform of the protein. T cell activation and latent HIV-1 reactivation induced by the positive control PHA also leads to an increase in the pro-apoptotic isoform of the protein (i.e. FAS exon 6 inclusion), providing further evidence that metformin indeed alters alternative splicing and likely facilitates latent HIV-1 reactivation [15].
Cumulatively, the results from these studies dramatically indicate that compounds such as methylene blue, sulforaphane, and retinoic that have been shown to not only correct aging defects in progeria cells but enhance T cell activation or latent HIV-1 reactivation do so via a common mechanism of AMPK activation that likely also involves correction of alternative splicing. Although no studies have been conducted to date, the application of metformin to progeria cells will likely beneficially alter alternative splicing, enhance mitochondrial function, and reverse accelerated aging defects in progeria cells, in addition to enhancing latent HIV-1 reactivation. That diseases such as progeria and the reversal of HIV-1 latency may be connected by a common pathway and that the activation of this pathway (via AMPK) by chemically distinct compounds represents a common mechanism of action would be unprecedented and undoubtedly warrant a reevaluation of disease interconnectedness.
https://www.linkedin.com/pulse/ampk-activator-metformin-alters-gene-splicing-humans-potential?trk=mp-reader-card
References:
Another recent post of mine (see below) from LinkedIn on a study that is definitely a HUGE plus in making my hypothesis on treating/reversing progeria that much more real. Metformin, a widely-prescribed anti-diabetic drug derived from the plant Galega officinalis (a plant that has been used to treat symptoms of diabetes mellitus dating back to the Middle Ages) that has been shown to increase the lifespan and healthspan of several organisms, corrects gene splicing in cells from patients with the autosomal-dominant muscle wasting disease myotonic dystrophy type I (DM1). Progeria is an autosomal-dominant disease like DM1 and both are characterized by faulty gene splicing. What's super interesting about this study is that metformin also beneficially altered gene splicing in human diabetic patients taking metformin who didn't have DM1. Just as methylene blue, retinoic acid (vitamin A metabolite), and sulforaphane (broccoli sprout compound) all activate AMPK and reverse aging defects in progeria cells, I think I was the first one to predict via my publications that metformin (and other AMPK activators) may correct gene splicing and reverse aging defects in progeria cells by activating AMPK. Because this study shows that metformin can do just that (alter gene splicing) in the disease DM1 and in normal diabetics and because metformin also enhances the reactivation of dormant HIV-1 infected T cells, it seems that maybe my hypothesis of disease interconnectedness may turn out to be true. IF IT DOES......................:-)
AMPK activator Metformin alters gene splicing in humans: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation
A recent study published online in the Journal Molecular Therapy Nucleic Acids in November of 2015 provided startling evidence that metformin, a widely-prescribed anti-diabetic drug derived from the plant Galega officinalis (a plant that has been used to treat symptoms of diabetes mellitus dating back to the Middle Ages) that has been shown to increase the lifespan and healthspan of several organisms, corrects alternative splicing defects in primary myoblasts derived from patients with myotonic dystrophy type I (DM1) as well as in derivatives of embryonic stem cells that carry the DM1 mutation in an AMPK-dependent manner. Strikingly, metformin also beneficially altered the splicing of the insulin receptor gene in diabetic patients who were taking metformin but who did not have DM1, in typical therapeutic dosages [1].
DM1, a genetic disorder inherited in an autosomal dominant fashion, is characterized by muscle weakness and wasting, cardiac conduction abnormalities, and myotonia (prolonged muscle contraction) [2]. According to the NIH, “ ‘Autosomal’ means that the gene in question is located on one of the numbered, or non-sex, chromosomes. ‘Dominant’ means that a single copy of the disease-associated mutation is enough to cause the disease.” [3]. DM1 is known as a trinucelotide repeat disorder, a condition in which there is an expansion or repeat of two or three nucleotides in a particular gene that can lead to manifestation of disease if the sequence of repeats extends beyond a certain number. For example, the affected gene in DM1, called DMPK, codes for a protein that is primarily expressed in skeletal muscle. A repeat expansion consisting of the cytosine-thymine-guanine (CTG) triplet between 5 and 37 repeats is considered normal while repeats exceeding 50 nearly always results in symptomatic disease [4].
Interestingly, DM1 is also known as a model of spliceopathy (i.e. misregulated alternative splicing), and is characterized by defects in the alternative RNA splicing machinery, generating alternatively spliced isoforms that contribute to the severity of the disease, including insulin resistance [1]. Using mesodermal precursor cells (MPCs) that were derived from embryonic stem cells from an embryo that was a DM1-gene carrier, the authors initially showed that metformin corrected splicing defects in the insulin receptor (INSR) gene by increasing the proportion of INSR with exon 11 inclusion in both DM1 MPCs and in wild-type MPCs, indicating that metformin has the ability to positively regulate alternative splicing in normal cells as well as in mutated cells [1]. Metformin also corrected alternative splicing defects in the DM1-associated genes TNNT2 and Cln1 by lowering the percentage of exon 5 inclusion in TNNT2 and lowering the percentage of exon 7a inclusion in Clcn1 to levels similar to wild-type MPCs [1]. Additionally, using deep RNA sequencing, the authors also demonstrated that metformin altered gene expression and alternative splicing of a large number of genes in DM1 MPCs, with metformin affecting the expression of a total of 1,171 genes and regulating eighty-nine splicing events and 416 exons above 10% [1].
Metformin’s mechanism of action has been shown to be dependent on its ability to activate the master metabolic regulator AMPK by increasing the intracellular AMP/ATP ratio, thus inducing a compensatory cellular stress response [5]. Indeed, the authors showed that metformin specifically inhibited complex I of the mitochondrial electron transport chain in DM1 MPCs, leading to an increase in the AMP/ATP ratio [1]. Additionally, by using AICAR, a pharmacological AMPK activator widely used in studies to asses the effects of AMPK activation, the authors showed that treatment of DM1 MPCs with AICAR altered exon inclusion on five of the splicing events most regulated by metformin (MDM4 exon 7 [decreased exon inclusion], GPCPD1 exon 5 [decreased exon inclusion], CCNL2 exon 7 [increased exon inclusion], RAGE exon 3 [decreased exon inclusion], and ZFAND1 exon 3 [decreased exon inclusion]) [1]. Such data provides compelling evidence that metformin alters alternative splicing via the activation of AMPK.
The authors however extended the analysis one step further, testing the effects of metformin treatment on alternative splicing events associated with muscle strength by using myoblasts from two different patients diagnosed with DM1 and two healthy patients. Interestingly, metformin beneficially altered the splicing of 6 genes (INSR exon 11, TNNT2 exon 5, ATP2A1 exon 22, DMD exon 71, DMD exon 78, and KIF13A exon 32), as evidenced by a shift in the isoform ratio towards control values [1].
Perhaps most importantly, however, was the verification of metformin’s effect on alternative splicing in vivo via the use of human subjects. A clinical trial was performed wherein 15 diabetic patients, who did not have DM1 but were currently taking metformin for more than a year (between 2.1 and 3 g/day), were recruited and the effects of metformin on alternative splicing were conducted on peripheral blood lymphocytes (PBLs). Strikingly, using quantitative PCR, the authors showed that metformin triggered the inclusion of INSR exon 11 in a clinical setting. However, when metformin was temporarily replaced by another diabetic drug that was shown in other experiments not to effect INSR exon 11 alternative splicing, INSR exon 11 inclusion was decreased. However, when the patients were placed back on metformin, INSR exon 11 inclusion increased, indicating that metformin also alters alternative splicing in vivo in human subjects. Curiously, metformin also decreased FAS (CD95) exon 6 exclusion in PBLs from treated patients, generating a shift from the anti-apoptotic to the pro-apoptotic protein isoform [1].
The results from this study represents an incredible example of how compounds as chemically distinct as metformin, retinoic acid, sulforaphane, and likely many others share a common indirect mechanism of action of AMPK activation, leading to correction of gene splicing in genetic disorders characterized by autosomal dominance (e.g. progeria and DM1), reactivation of latent viral infections to facilitate immune system eradication (e.g. HIV-1 latency), and regulation of cellular processes that are almost universally associated with both normal and accelerated aging (e.g. mitochondrial dysfunction and telomere erosion).
Indeed, methylene blue has recently been shown to reverse accelerated aging defects, correct mitochondrial function, increase PGC1a levels, and increase lamin A mRNA (evidence of alteration of alternative splicing) in fibroblasts derived from patients with Hutchinson-Gilford progeria syndrome, an accelerated aging disease caused by aberrant alternative splicing of the LMNA gene [6]. Methylene blue has also shown been shown to delay cellular senescence in lung cells via AMPK activation, decrease telomere erosion, and reactivate latent HIV-1 via photosensitization (see prior post for references). Similarly, metformin has also been shown to enhance mitochondrial function through enhancing an AMPK-mediated PGC1a upregulation, correct gene splicing in an AMPK-dependent manner in DM1, increase lifespan and healthspan in several organisms, and synergize with bryostatin to enhance the reactivation of latent HIV-1 [1,7,8]. Interestingly, bryostatin, a protein kinase C activator, was also shown to phosphorylate and activate AMPK, implying that bryostatin is an indirect AMPK activator as well [8].
This common theme of AMPK activation also extends to sulforaphane, the broccoli sprout compound that was recently found to also reverse aging defects in progeria cells [9]. Sulforaphane was shown to enhance the autophagic degradation of progerin (mutant protein) in cells derived from progeria patients, increase the proportions of lamin A (normal protein) yet decrease those of progerin in progeria cells, stimulate the immune response against cancer cells, inhibit scrapie prion protein accumulation by activating AMPK, and inhibit two epigenetic factors (EZH2 and SUV39H1) that keep HIV-1 dormant in infected T cells that are also dysregulated in progeria cells (see prior post for references). As AMPK is essential for T cell activation, metformin has been shown to enhance latent HIV-1 reactivation, increase the formation of cytotoxic memory CD8+ T cells (targets and kills viruses and cancer cells), induce autophagy by activating the AMPK-ULK1 pathway, and modulate the repressive epigenetic factors EZH2 and SUV39H1 [8,10-13].
The commonality of AMPK activation between metformin and sulforaphane also extends to retinoic acid (and/or its derivatives), a vitamin A metabolite that activates AMPK and was recently shown to reverse aging defects in progeria cells, decrease progerin mRNA in progeria cells (evidence of alteration of alternative splicing), regulate the same gene splicing factors that play a role in both HGPS and latent HIV-1 reactivation, enhance T cell activation, and act synergistically with other agents to reactivate latent HIV-1 [14, see prior post for other references]. Again, AMPK activation is likely playing a critical role in each of these processes, as AMPK activation beneficially alters alternative splicing and is essential for T cell activation and thus latent HIV-1 reactivation.
Furthermore, in the 2015 Molecular Therapy Nucleic Acids study referenced above, metformin decreased FAS (CD95) exon 6 exclusion in PBLs from treated patients, generating a shift from the anti- to the pro-apoptotic isoform of the protein. T cell activation and latent HIV-1 reactivation induced by the positive control PHA also leads to an increase in the pro-apoptotic isoform of the protein (i.e. FAS exon 6 inclusion), providing further evidence that metformin indeed alters alternative splicing and likely facilitates latent HIV-1 reactivation [15].
Cumulatively, the results from these studies dramatically indicate that compounds such as methylene blue, sulforaphane, and retinoic that have been shown to not only correct aging defects in progeria cells but enhance T cell activation or latent HIV-1 reactivation do so via a common mechanism of AMPK activation that likely also involves correction of alternative splicing. Although no studies have been conducted to date, the application of metformin to progeria cells will likely beneficially alter alternative splicing, enhance mitochondrial function, and reverse accelerated aging defects in progeria cells, in addition to enhancing latent HIV-1 reactivation. That diseases such as progeria and the reversal of HIV-1 latency may be connected by a common pathway and that the activation of this pathway (via AMPK) by chemically distinct compounds represents a common mechanism of action would be unprecedented and undoubtedly warrant a reevaluation of disease interconnectedness.
https://www.linkedin.com/pulse/ampk-activator-metformin-alters-gene-splicing-humans-potential?trk=mp-reader-card
References:
- Laustriat D, Gide J, Barrault L, et al. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin. Mol Ther Nucleic Acids. 2015 Nov 3;4:e262.
- http://www.ncbi.nlm.nih.gov/books/NBK1165/
- http://ghr.nlm.nih.gov/glossary=autosomaldominant
- Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):358-67.
- Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011 Sep 2;13(9):1016-23.
- Xiong ZM, Choi JY, Wang K, et al. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell. 2015 Dec 14. doi: 10.1111/acel.12434.
- Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012 Apr;11(2):230-41.
- Mehla R, Bivalkar-Mehla S, Zhang R, et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One. 2010 Jun 16;5(6):e11160.
- Gabriel D, Roedl D, Gordon LB, Djabali K. Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts. Aging Cell. 2015 Feb;14(1):78-91.
- Pearce EL, Walsh MC, Cejas PJ, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009 Jul 2;460(7251):103-7.
- Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011 Jan 28;331(6016):456-61.
- Bao B, Wang Z, Ali S, et al. Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res (Phila). 2012 Mar;5(3):355-64.
- Xin Li, Juncheng Wei, Satoko Matsumura, Yuqi Guo, Huawei Yuan. Epigenetic alterations in the multifaceted inhibitory effects of metformin on castration resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4033. doi:10.1158/1538-7445.AM2014-4033.
- Pellegrini C, Columbaro M, Capanni C, et al. All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype. Oncotarget. 2015 Oct 6;6(30):29914-28.
- C Liu, J Cheng, and J D Mountz. Differential expression of human Fas mRNA species upon peripheral blood mononuclear cell activation. Biochem J. 1995 Sep 15; 310(Pt 3): 957–963.
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