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Find video protocols related to scientific articles indexed in Pubmed.
Xenotransplantation of human fetal adipose tissue: a model of in vivo adipose tissue expansion and adipogenesis.
J. Lipid Res.
PUBLISHED: 09-05-2014
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Obesity during childhood and beyond may have its origins during fetal or early postnatal life. At present, there are no suitable in vivo experimental models to study factors that modulate or perturb human fetal white adipose tissue expansion, remodeling, development, adipogenesis, angiogenesis, or epigenetics. We have developed such a model. It involves the xenotransplantation of mid-gestation human white adipose tissue into the renal subcapsular space of immunocompromised SCID-beige mice. After an initial latency period of approximately two weeks, the tissue begins expanding. The xenografts are healthy and show robust expansion and angiogenesis for at least two months following transplantation. Data and cell size and gene expression are consistent with active angiogenesis. The xenografts maintain the expression of genes associated with differentiated adipocyte function. In contrast to the fetal tissue, adult human white adipose tissue does not engraft. The long-term viability and phenotypic maintenance of fetal adipose tissue following xenotransplantation may be a function of its autonomous high rates of adipogenesis and angiogenesis. Through the manipulation of the host mice, this model system offers the opportunity to study the mechanisms by which nutrients and other environmental factors affect human adipose tissue development and biology.
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Chronic Exposure to Low-Dose Arsenic Modulates Lipogenic Gene Expression in Mice.
J. Biochem. Mol. Toxicol.
PUBLISHED: 08-23-2014
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Arsenic, a ubiquitous environmental toxicant, can affect lipid metabolism through mechanisms that are not well understood. We studied the effect of arsenic on serum lipids, lipid-regulating genes, and transcriptional regulator sterol regulatory element binding protein 1c (SREBP-1c). C57BL/6 mice were administered 0 or 100 ppb sodium arsenite in drinking water for 5 weeks. Arsenic exposure was associated with decreased liver weight but no change in body weight. Serum triglycerides level fell in arsenic-exposed animals, but not in fed animals, after short-term fasting. Hepatic expression of SREBP-1c was reduced in arsenic-exposed fed animals, with a 16-fold change in reduction. Similar effects were seen for SREBP-1c in white adipose tissue. However, fasting resulted in dissociation of the expression of SREBP-1c and its targets, and SREBP-1c protein content could not be shown to correlate with its mRNA expression. We conclude that arsenic modulates hepatic expression of genes involved in lipid regulation through mechanisms that are independent of SREBP-1c expression.
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Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2).
FASEB J.
PUBLISHED: 09-26-2013
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The mechanistic target of rapamycin (mTOR) exists in two complexes that regulate diverse cellular processes. mTOR complex 1 (mTORC1), the canonical target of rapamycin, has been well studied, whereas the physiological role of mTORC2 remains relatively uncharacterized. In mice in which the mTORC2 component Rictor is deleted in liver [Rictor-knockout (RKO) mice], we used genomic and phosphoproteomic analyses to characterize the role of hepatic mTORC2 in vivo. Overnight food withdrawal followed by refeeding was used to activate mTOR signaling. Rapamycin was administered before refeeding to specify mTORC2-mediated events. Hepatic mTORC2 regulated a complex gene expression and post-translational network that affects intermediary metabolism, ribosomal biogenesis, and proteasomal biogenesis. Nearly all changes in genes related to intermediary metabolic regulation were replicated in cultured fetal hepatocytes, indicating a cell-autonomous effect of mTORC2 signaling. Phosphoproteomic profiling identified mTORC2-related signaling to 144 proteins, among which were metabolic enzymes and regulators. A reduction of p38 MAPK signaling in the RKO mice represents a link between our phosphoproteomic and gene expression results. We conclude that hepatic mTORC2 exerts a broad spectrum of biological effects under physiological conditions. Our findings provide a context for the development of targeted therapies to modulate mTORC2 signaling.-Lamming, D. W., Demirkan, G., Boylan, J. M., Mihaylova, M. M., Peng, T., Ferreira, J., Neretti, N., Salomon, A., Sabatini, D. M., Gruppuso, P. A. Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2).
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Resveratrol inhibits protein translation in hepatic cells.
PLoS ONE
PUBLISHED: 08-10-2011
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Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrols effects have yet to be elucidated. Because repression of translation shares many of resveratrols beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self-phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2?. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling.
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Mentoring fathers of children newly diagnosed with T1DM.
MCN Am J Matern Child Nurs
PUBLISHED: 06-29-2011
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To pilot test a social support intervention for fathers of children <13 years old newly diagnosed with type 1 diabetes mellitus (T1DM).
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Phosphoproteomic profiling of in vivo signaling in liver by the mammalian target of rapamycin complex 1 (mTORC1).
PLoS ONE
PUBLISHED: 04-21-2011
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Our understanding of signal transduction networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. In the present study, we focused on signaling through the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is at the center of a nutrient- and growth factor-responsive cell signaling network. Though studied extensively, the mechanisms involved in many mTORC1 biological functions remain poorly understood.
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The physiology and pathophysiology of rapamycin resistance: implications for cancer.
Cell Cycle
PUBLISHED: 04-01-2011
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Rapamycin is an inhibitor of the mammalian Target of Rapamycin, mTOR, a nutrient-sensing signaling kinase and a key regulator of cell growth and proliferation. While rapamycin and related compounds have anti-tumor activity, a prevalent characteristic of cancer cells is resistance to their anti-proliferative effects. Our studies on nutrient regulation of fetal development showed that hepatocyte proliferation in the late gestation fetal rat is resistant to rapamycin. Extension of these studies to other tissues in the fetal and neonatal rat indicated that rapamycin resistance is a characteristic of normal cell proliferation in the growing organism. In hepatic cells, ribosomal biogenesis and cap-dependent protein translation were found to be relatively insensitive to the drug even though mTOR signaling was highly sensitive. Cell cycle progression was also resistant at the level of cyclin E-dependent kinase activity. Studies on the effect of rapamycin on gene expression in vitro and in vivo demonstrated that mTOR-mediated regulation of gene expression is independent of effects on cell proliferation and cannot be accounted for by functional regulation of identifiable transcription factors. Genes involved in cell metabolism were overrepresented among rapamycin-sensitive genes. We conclude that normal cellular proliferation in the context of a developing organism can be independent of mTOR signaling, that cyclin E-containing complexes are a critical locus for rapamycin sensitivity, and that mTOR functions as a modulator of metabolic gene expression in cells that are resistant to the anti-proliferative effects of the drug.
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Hepatocyte nuclear factor 4? gene mutation associated with familial neonatal hyperinsulinism and maturity-onset diabetes of the young.
J. Pediatr.
PUBLISHED: 01-04-2011
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Neonatal macrosomia and hyperinsulinemic hypoglycemia with strong family history of diabetes may indicate monogenic diabetes. Here we report a family in which 4 individuals in 3 generations were found to have a mutation (Arg80Gln) in hepatocyte nuclear factor 4?. Genetic testing was a factor in choosing sulfonylurea therapy for diabetes.
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The mechanism of ascorbic acid-induced differentiation of ATDC5 chondrogenic cells.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 06-08-2010
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The ATDC5 cell line exhibits a multistep process of chondrogenic differentiation analogous to that observed during endochondral bone formation. Previous investigators have induced ATDC5 cells to differentiate by exposing them to insulin at high concentrations. We have observed spontaneous differentiation of ATDC5 cells maintained in ascorbic acid-containing alpha-MEM. A comparison of the differentiation events in response to high-dose insulin vs. ascorbic acid showed similar expression patterns of key genes, including collagen II, Runx2, Sox9, Indian hedgehog, and collagen X. We took advantage of the action of ascorbic acid to examine signaling events associated with differentiation. In contrast to high-dose insulin, which downregulates both IGF-I and insulin receptors, there were only minimal changes in the abundance of these receptors during ascorbic acid-induced differentiation. Furthermore, ascorbic acid exposure was associated with ERK activation, and ERK inhibition attenuated ascorbic acid-induced differentiation. This was in contrast to the inhibitory effect of ERK activation during IGF-I-induced differentiation. Inhibition of collagen formation with a proline analog markedly attenuated the differentiating effect of ascorbic acid on ATDC5 cells. When plates were conditioned with ATDC5 cells exposed to ascorbic acid, ATDC5 cells were able to differentiate in the absence of ascorbic acid. Our results indicate that matrix formation early in the differentiation process is essential for ascorbic acid-induced ATDC5 differentiation. We conclude that ascorbic acid can promote the differentiation of ATDC5 cells by promoting the formation of collagenous matrix and that matrix formation mediates activation of the ERK signaling pathway, which promotes the differentiation program.
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Commentary: the unsustainable cost of undergraduate medical education: an overlooked element of U.S. health care reform.
Acad Med
PUBLISHED: 06-04-2010
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The cost of undergraduate medical education has been rising at more than twice the rate of inflation in recent years. A leveling off of the cost of medical education is unlikely to be realized any time soon. Rather, current economic circumstances are likely to further increase the upward pressure on medical schools seeking to correct budgetary shortfalls. Median student debt burden has increased by more than 50% from 1998 to 2008. All of this portends a negative impact on the diversity of the national medical student body and the ability of medical schools to meet workforce needs, including those necessary to the effective provision of primary care. As challenging as the high indebtedness issue may be, it is not insolvable. Current trends could be relieved by increasing financial assistance, improving the quality and availability of loan programs, and reducing the cost of attendance. Achieving the latter through foreshortening of the course of study is both feasible and potentially effective. All of these measures could and should be addressed as integral components of health care reform if we are to address the shortage of primary care physicians and other workforce needs.
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Implementation of a longitudinal mentored scholarly project: an approach at two medical schools.
Acad Med
PUBLISHED: 02-26-2010
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An increasing number of medical schools have implemented or are considering implementing scholarly activity programs as part of their undergraduate medical curricula. The goal of these programs is to foster students analytical skills, enhance their self-directed learning and their oral and written communication skills, and ultimately to train better physicians. In this article, the authors describe the approach to implementing scholarly activities at a school that requires this activity and at a school where it is elective. Both programs have dealt with significant challenges including orienting students to a complex activity that is fundamentally different than traditional medical school courses and clerkships, helping both students and their mentors understand how to "stay on track" and complete work, especially during the third and fourth years, and educating students and mentors about the responsible conduct of research, especially involving human participants. Both schools have found the implementation process to be evolutionary, requiring experience before faculty could significantly improve processes. A required scholarly activity has highlighted the need for information technology (IT) support, including Web-based document storage and student updates, as well as automatic e-mails alerting supervisory individuals to student activity. Directors of the elective program have found difficulty with both ensuring uniform outcomes across different areas of study and leadership changes in a process that has been largely student-driven. Both programs have found that teamwork, regular meetings, and close communication have helped with implementation. Schools considering the establishment of a scholarly activity should consider these factors when designing programs.
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Encouraging scholarship: medical school programs to promote student inquiry beyond the traditional medical curriculum.
Acad Med
PUBLISHED: 02-26-2010
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Many medical curricula now include programs that provide students with opportunities for scholarship beyond that provided by their traditional, core curricula. These scholarly concentration (SC) programs vary greatly in focus and structure, but they share the goal of producing physicians with improved analytic, creative, and critical-thinking skills. In this article, the authors explore models of both required and elective SC programs. They gathered information through a review of medical school Web sites and direct contact with representatives of individual programs. Additionally, they discuss in-depth the SC programs of the Warren Alpert Medical School of Brown University; the University of South Florida College of Medicine; the University of California, San Francisco; and Stanford University School of Medicine. The authors describe each programs focus, participation, duration, centralization, capstone requirement, faculty involvement, and areas of concentration. Established to address a variety of challenges in the U.S. medical education system, these four programs provide an array of possible models for schools that are considering the establishment of an SC program. Although data on the impact of SC programs are lacking, the authors believe that this type of program has the potential to significantly impact the education of medical students through scholarly, in-depth inquiry and longitudinal faculty mentorship.
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Required vs. elective research and in-depth scholarship programs in the medical student curriculum.
Acad Med
PUBLISHED: 02-26-2010
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The ability to understand and integrate new knowledge into clinical practice is a necessary quality of good physicians. Student participation in in-depth scholarship could enhance this skill in physicians while also creating a larger cadre of physician-scientists prepared to advance the field of medicine. However, because no definitive data exist demonstrating that in-depth scholarship in medical school leads to improved patient care or to productive academic careers, whether such scholarship should be required as part of the medical school curriculum is unclear. In this article, the authors present both sides of this debate. Theoretical benefits to students of a required scholarly program include closer mentorship by individual faculty, enhanced capabilities in critical interpretation of research findings, and increased confidence to investigate conundrums encountered in clinical care. Society may also benefit by having physicians available to create and apply new knowledge related to biomedicine. These theoretical benefits must be balanced, however, by pragmatic considerations of required scholarly projects including their impact on medical school applications, their effect on the medical curriculum, their costs, the availability of mentors, and their effects on the schools educational culture.
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Regulation of gene expression in hepatic cells by the mammalian Target of Rapamycin (mTOR).
PLoS ONE
PUBLISHED: 01-12-2010
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We investigated mTOR regulation of gene expression by studying rapamycin effect in two hepatic cell lines, the non-tumorigenic WB-F344 cells and the tumorigenic WB311 cells. The latter are resistant to the growth inhibitory effects of rapamycin, thus providing us with an opportunity to study the gene expression effects of rapamycin without confounding effects on cell proliferation.
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Social Support to Empower Parents (STEP): an intervention for parents of young children newly diagnosed with type 1 diabetes.
Diabetes Educ
PUBLISHED: 12-16-2009
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The purpose of this study was to test the efficacy of a social support intervention with parents of children <13 years old newly diagnosed with type 1 diabetes mellitus (T1DM).
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Redesigning the clinical curriculum at the Warren Alpert Medical School of Brown University.
Med Health R I
PUBLISHED: 10-22-2009
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The proposed clinical curriculum in Years 3 and 4 provides the opportunity to complete the process begun with the reform of the pre-clerkship curriculum in 2007. The redesign should produce an educational process which not only more adequately prepares students for the future, but helps produce leaders in multiple fields of medicine and re-establishes Brown as an innovator in medical education.
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Disorders of the growth plate.
Curr Opin Endocrinol Diabetes Obes
PUBLISHED: 09-23-2009
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To summarize the recent advances in our understanding of the majors genes involved in chondrogenesis and their molecular mechanisms.
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Rapamycin response in tumorigenic and non-tumorigenic hepatic cell lines.
PLoS ONE
PUBLISHED: 07-29-2009
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The mTOR inhibitor rapamycin has anti-tumor activity across a variety of human cancers, including hepatocellular carcinoma. However, resistance to its growth inhibitory effects is common. We hypothesized that hepatic cell lines with varying rapamycin responsiveness would show common characteristics accounting for resistance to the drug.
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Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 04-28-2009
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Linear growth in children is sensitive to nutritional status. Amino acids, in particular leucine, have been shown to regulate cell growth, proliferation, and differentiation through the mammalian target of rapamycin (mTOR), a nutrient-sensing protein kinase. Having recently demonstrated a role for mTOR in chondrogenesis, we hypothesized that leucine restriction, acting through mTOR, would inhibit growth plate chondrocyte proliferation and differentiation. The effect of leucine restriction was compared with that of the specific mTOR inhibitor, rapamycin. Leucine restriction produced a dose-dependent inhibition of fetal rat metatarsal explant growth. This was accounted by reduced cell proliferation and hypertrophy but not apoptosis. mTOR activity, as reflected by ribosomal protein S6 phosphorylation, was only partially inhibited by leucine restriction, whereas rapamycin abolished S6 phosphorylation. In chondrogenic ATDC5 cells, leucine restriction inhibited cell number, proteoglycan accumulation, and collagen X expression despite minimal inhibition of mTOR. Microarray analysis demonstrated that the effect of leucine restriction on ATDC5 cell gene expression differed from that of rapamycin. Out of 1,571 genes affected by leucine restriction and 535 genes affected by rapamycin, only 176 genes were affected by both. These findings indicate that the decreased chondrocyte growth and differentiation associated with leucine restriction is only partly attributable to inhibition of mTOR signaling. Thus nutrient restriction appears to directly modulate bone growth through unidentified mTOR-independent mechanisms in addition to the well-characterized mTOR nutrient-sensing pathway.
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The effect of rapamycin on bone growth in rabbits.
J. Orthop. Res.
PUBLISHED: 04-22-2009
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mTOR is a nutrient-sensing protein kinase that regulates numerous cellular processes. Our prior studies using the mTOR inhibitor, rapamycin, indicate an important role for mTOR in chondrogenesis. We extended our observations to a physiological, in vivo model of bone growth, direct infusion of rapamycin into the proximal tibial growth plates of rabbits. Rapamycin or DMSO vehicle was infused directly into growth plates by an osmotic minipump for 8 weeks. Tibial growth was followed radiographically. At the end of the experiment, growth plates were recovered for histological analysis. Six animals were studied. No untoward effects of rapamycin infusion were found. Bone growth of limbs exposed to rapamycin was slower than control limbs, particularly during the period of most rapid growth. Histological analysis revealed that growth plate height in the rapamycin-infused limbs was reduced. Both the hypertrophic and proliferative zones were significantly smaller in the rapamycin-infused limbs. Direct infusion of rapamycin into proximal tibial growth plates decreased the size of the growth plate and inhibited overall long bone growth. Rapamycin appears to affect both the proliferative and hypertrophic zones of the tibial growth plate. Our results indicate that nutrients may exert a direct effect on long bone growth via mTOR-mediated modulation of chondrogenesis at the growth plate. and suggest that the possible inhibitory effects of rapamycin on skeletal growth warrant further attention before its use in children.
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Phosphoproteomic analysis of liver homogenates.
Methods Mol. Biol.
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Regulation of protein function via reversible phosphorylation is an essential component of cell signaling. Our ability to understand complex phosphorylation networks in the physiological context of a whole organism or tissue remains limited. This is largely due to the technical challenge of isolating serine/threonine phosphorylated peptides from a tissue sample. In the present study, we developed a phosphoproteomic strategy to purify and identify phosphopeptides from a tissue sample by employing protein gel filtration, protein strong anion exchange and strong cation exchange (SCX) chromatography, peptide SCX chromatography, and TiO(2) affinity purification. By applying this strategy to the mass spectrometry-based analysis of rat liver homogenates, we were able to identify with high confidence and quantify over 4,000 unique phosphopeptides. Finally, the reproducibility of our methodology was demonstrated by its application to analysis of the mammalian Target of Rapamycin (mTOR) signaling pathways in liver samples obtained from rats in which hepatic mTOR was activated by refeeding following a period of fasting.
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The inhibitory effect of rapamycin on the oval cell response and development of preneoplastic foci in the rat.
Exp. Mol. Pathol.
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Oval cell activation occurs under conditions of severe liver injury when normal hepatocyte proliferation is blocked. Recent studies have shown that a subset of hepatocellular carcinomas expresses oval cell markers, suggesting that these cells are targets of hepatocarcinogens. However, the signaling pathways that control oval cell activation and proliferation are not well characterized. Based on the role of the nutrient signaling kinase complex, mTORC1, in liver development, we investigated the role of this pathway in oval cell activation. Oval cell proliferation was induced in male Fisher rats by a modification of the traditional choline deficient plus ethionine model (CDE) or by 2-acetylaminoflourene treatment followed by 2/3 partial hepatectomy with or without initiation by diethylnitrosamine. To assess the role of mTOR in the oval cell response and development of preneoplastic foci, the effect of the mTORC1 inhibitor, rapamycin, was studied in all models. Rapamycin induced a significant suppression of the oval cell response in both models, an effect that coincided with a decrease in oval cell proliferation. Rapamycin administration did not affect the abundance of neutrophils or natural killer cells in CDE-treated liver or the expression of key cytokines. Gene expression studies revealed the fetal hepatocyte marker MKP-4 to be expressed in oval cells. In an experimental model of hepatic carcinogenesis, rapamycin decreased the size of preneoplastic foci and the rate of cell proliferation within the foci. mTORC1 signaling plays a key role in the oval cell response and in the development of preneoplastic foci. This pathway may be a target for the chemoprevention of hepatocellular carcinoma.
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Postnatal liver growth and regeneration are independent of c-myc in a mouse model of conditional hepatic c-myc deletion.
BMC Physiol.
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The transcription factor c-myc regulates genes involved in hepatocyte growth, proliferation, metabolism, and differentiation. It has also been assigned roles in liver development and regeneration. In previous studies, we made the unexpected observation that c-Myc protein levels were similar in proliferating fetal liver and quiescent adult liver with c-Myc displaying nucleolar localization in the latter. In order to investigate the functional role of c-Myc in adult liver, we have developed a hepatocyte-specific c-myc knockout mouse, c-mycfl/fl;Alb-Cre.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.