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Nathan Goodyear

Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2 | npj Precision Oncology - 0 views

  • Chen et al. have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.
  • Ascorbic acid (the reduced form of vitamin C) is specifically transported into cells by sodium-dependent vitamin C transporters (SVCTs)
  • SVCT-1 is predominantly expressed in epithelial tissues
  • ...41 more annotations...
  • whereas the expression of SVCT-2 is ubiquitous
  • differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.
  • high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.
  • Hepatocellular carcinoma (HCC)
  • The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells
  • DNA double-strand damage was found following VC treatment
  • DNA damage was prevented by NAC
  • Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight
  • Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs
  • VC is one of the numerous common hepatoprotectants.
  • Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells
  • we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.
  • Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients
  • Median DFS time for VC users was 25.2 vs. 18 months for VC non-users
  • intravenous VC use is linked to improved DFS in HCC patients.
  • In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo
    • Nathan Goodyear
       
      the authors here made similar mistakes to the Mayo authors i.e. under doses here in this study.  They dosed at only 2 grams IVC.  A woefully low dose of IVC.
  • Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.
    • Nathan Goodyear
       
      positive results despite a low dose used.
    • Nathan Goodyear
       
      Their comfort zone was 1mM.  They should have targeted 20-40 mM.
  • Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy
  • As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity
  • we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs
  • SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC
  • CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance
  • we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death
  • as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs
  • In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells
  • we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo
  • Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation
    • Nathan Goodyear
       
      so, exclude the benefit to patients until the exact mechanism of action, which will never be fully elicited?!?!?
  • Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy
    • Nathan Goodyear
       
      Terribly inadequate dose.  Target is 20-40 mM which other studies have found occur with 50-75 grams of IVC.
  • several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS
  • high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo
  • high recurrence rate and heterogeneity
  • tumor progression, metastasis, and chemotherapy-resistance
  • SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues
  • high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior
  • SVCT-2 is enriched in liver CSCs
  • these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.
  • pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration
  • The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner
  • VC and cisplatin combination further caused cell apoptosis in tumor xenograft
  • These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response
  • qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs
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    IV vitamin C in vitro and in vivo found to "preferentially" eradicate cancer stem cells.  In addition, IV vitamin C was found to be adjunctive to chemotherapy, found to be hepatoprotectant.  This study also looked at SVCT-2, which is the transport protein important in liver C uptake.
Nathan Goodyear

High Progesterone Receptor Expression in Prostate Cancer Is Associated with Clinical Failure - 0 views

  • Currently, there is a general agreement of PGR presence in the stromal cells of PCa
  • expressed in both stromal and tumor cells of the PCa tissue
  • In univariate analysis, a high density level of PGR in both TE and TS was associated with CF
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  • High density level of PGR in the TE was an independent prognostic factor for CF.
  • Our large-sized study demonstrates a wide distribution of PGR in stromal and epithelial cells of both benign and malignant prostate tissue
  • there seems to be a general agreement of PGR presence in the stromal cells of PCa
  • In line with our findings, several have also reported a high PGR expression in TE of PCa [9,10,23,25]. In contrast, others have demonstrated a total lack of PGR expression in TE
  • the actions of progesterone are tissue specific
  • In our work univariate analysis demonstrated a high PGR expression in TS to be associated with clinical failure in PCa patients. So far we have not yet demonstrated the mechanism underlying this association
  • Several non-genomic proliferative actions of progesterone have been proposed in tumor cells of other organs, including breast [35–37], astrocytoma [38] and osteosarcoma [39] cell lines. However, such results are contradicted by suggestions of anti-proliferative actions of progesterone in endometrial cancer
  • Yu et al. found PGR to be negatively regulating stromal cell proliferation in vitro
  • high PGR density level in TE was associated with CF in patients with Gleason score ≥ 7
  • Bonkhoff et al. have suggested progressive emergence of PGR during PCa progression and metastasis
  • Latil and co-workers found a decreased PGR expression in clinically localized tumors and increased PGR expression in hormone-refractory tumors, when compared with normal prostate tissue
  • Our findings provide further support to these findings, indicating that PGR plays a role in the pathogenesis of PCa
  • Ki67 and PGR in TE were correlated with CF (S3 Text), indicating an association between PGR and proliferative activity
  • The mechanism behind the PGR up-regulation in PCa has not yet been elucidated
  • The PGR is, like the glucocorticoid receptor, similar to androgen receptor with 88% sequence homology in the ligand-binding domain
  • progesterone induced expression of androgen receptor-regulated genes could be a potential mechanism contributing to the development of castrate resistant PCa
  • A possibility of different roles by the two PGR isoforms in normal prostate tissue and PCa, as is suggested for the estrogen receptors [13], must also be taken into account
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    STudy finds that increased Progesterone receptor expression on epithelial and stromal cells is associated with increased clinical failure of therapy.  Several proposed mechanisms: 88% homologous with androgen receptor suggesting cross-stimulation and via progesterone induced increased androgen receptor gene stimulation i.e. epigenetics.
Nathan Goodyear

Lipopolysaccharide (LPS) potentiates hydrogen peroxide toxicity in T98G astrocytoma cells by suppression of anti-oxidative and growth factor gene expression - 0 views

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    good review of proposed mechanism of how LPS aids in cell death of astrocytes in vivo: LPS damages the endothelium of the BBB, leading to increase permeability.  This exposes astrocytes to LPS directly.  LPS suppressed genetic expression of antioxidant genes.  LPS stimulates cytokine production, including the production of H2O2 from microglial cells in the brain.  An up regulation of iNOS occurs and in the presence of weakened ability to protect against NO and its metabolites occurs.  
Nathan Goodyear

The Single Nucleotide Polymorphism Gly482Ser in the PGC-1α Gene Impairs Exercise-Induced Slow-Twitch Muscle Fibre Transformation in Humans - 0 views

  • Oxidative slow-twitch type I fibres (henceforth briefly called ‘slow fibres’) contain MHC-Iβ. They use oxidative phosphorylation (OXPHOS) to generate ATP and are thus highly fatigue resistant and preferentially activated during endurance exercise. Slow fibres comprise high amounts of mitochondria, myoglobin and lipid droplets, and are well supplied by capillaries
  • there are three types of fast-twitch fibres (types IIA, IID/X, IIB, with the corresponding MHC isoforms IIa, IId/x, IIb) which are all used for rapid high-force generation. Oxidative-glycolytic fast-twitch type IIA fibres have intermediate amounts of mitochondria, lipid droplets and capillaries, and are intermediately resistant to fatigue (as compared to type I and types IIB and IID/X). Glycolytic fast-twitch type IID/X fibres are poor in mitochondria, lipids and capillaries and more susceptible to fatique than type IIA. Glycolytic fast-twitch type IIB fibres have the lowest amounts of mitochondria, lipid droplets and capillaries, but generate the highest contraction velocities
  • Several studies have shown that PGC-1α is upregulated after endurance training
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  • upregulation of PGC-1α expression enhances and/or maintains mitochondrial biogenesis, eventually leading to an increased mitochondrial content of the muscle fibres.
  • PGC-1α also plays an important role in the pathogenesis of insulin resistance and T2D
  • carriers of the Gly482Ser SNP have a reduced cardiorespiratory fitness and a higher risk for metabolic syndrome and T2D
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    Those that carry the risk SNP for Gly482Ser for the PGC-1alpha gene dont' transform type II to type I and thus decrease the effectiveness of aeorbic exercise training, decreased oxidative phosphorylation, decreased lipid oxidation, increased lipid accumulaiton in muscle, and increased risk of IR, obesity, and diabetes.
Nathan Goodyear

A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue - 0 views

  • In skeletal muscle, HDAC4 has been found to be exported from the nucleus during exercise, suggesting that removal of the transcriptional repressive function could be a mechanism for exercise adaptation [50]. For HDAC4, we observed increased levels of DNA methylation and a simultaneous decrease in mRNA expression in adipose tissue in response to the exercise intervention. Additionally, the functional experiments in cultured adipocytes suggested increased lipogenesis when Hdac4 expression was reduced
  • NCOR2 also exhibited increased levels of DNA methylation and a simultaneous decrease in mRNA expression in adipose tissue in response to the exercise intervention, and furthermore we observed increased lipogenesis when Ncor2 expression was down regulated in the 3T3-L1 cell line. NCOR2 is a nuclear co-repressor, involved in the regulation of genes important for adipogenesis and lipid metabolism, and with the ability to recruit different histone deacetylase enzymes, including HDAC4
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    Study finds 6 month exercise program in men induced epigenetic change via DNA methylation of CPG islands in adipose cells effecting metabolism and altering obesity and type II diabetes risk.  The study looked at 2 genes: HDAC4 and NCOR2 and found that exercise decreased expression via methylation altering adipogenesis and lipid metabolism.
Nathan Goodyear

Amplification and Overexpression of Androgen Receptor Gene in Hormone-Refractory Prostate Cancer | Cancer Research - 0 views

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    Androgen resistance drives increase in AR gene activation and expression
Nathan Goodyear

Interaction between a peroxisome proliferator-activated receptor γ gene polymorphism and dietary fat intake in relation to body mass - 0 views

  • uniform dietary recommendations may not be appropriate for all individuals
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    Peroxisome proliferator-activated receptor gamma plays an important role in obesity and fat generation.  In this study, they showed how the genetic expression of different PPAR gamma genotypes results in altered physiologic response to fat intake in humans.  The interaction between genetics and the environment.
Nathan Goodyear

Sex-dependent changes in cerebellar thy - PubMed Mobile - 0 views

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    Thimerosal shown to disrupt thyroid gene expression in rat model.
Nathan Goodyear

Suppression of thyrotropin-releasing horm... [Neuroendocrinology. 1994] - PubMed - NCBI - 0 views

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    IL-1beta inhibits TRH gene activity.  Previous study has shown that IL-1 suppresses TSH production also.
Nathan Goodyear

Interleukin-1 inhibits thyrotrophin-induced hum... [J Endocrinol. 1989] - PubMed - NCBI - 0 views

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    IL-1, an inflammatory cytokine, down regulates TSH gene activity.  Take home: inflammation via IL-1 supresses TSH production.  
Nathan Goodyear

Transrepression of Inflammation -- Foley 4 (173): ec141 -- Science Signaling - 0 views

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    ER-beta agonist activity/agnoists inhibit inflammatory gene expression in microglia and astrocyte cells.
Nathan Goodyear

http://circ.ahajournals.org/content/circulationaha/107/18/2348.full.pdf - 0 views

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    histamine increased eNOS gene expression and thus NO production.
Nathan Goodyear

DNA methylation and cancer. - PubMed - NCBI - 0 views

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    hyper and hypo methylation known to be associated with carcinogenesis.  One carcinogenic potential of hypermethylation is through suppression of tumor suppression genes.
Nathan Goodyear

Annals of Internal Medicine | Gene-Diet Interactions in Brain Aging and Neurodegenerative Disorders - 0 views

  • it appears that dietary restriction promotes neuronal survival, plasticity, and even neurogenesis by inducing a mild cellular stress response that involves activation of genes that encode proteins designed to promote neuronal growth and surviva
  • Studies of animal models of Alzheimer disease and Parkinson disease have shown that, by decreasing homocysteine levels, dietary folic acid can be neuroprotective
  • The current average daily calorie intake of Americans is approximately 2700 for women and more than 3000 for men
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    what you eat and how many calories you eat effects you brain and your risk of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease.
Nathan Goodyear

Inhibitory effect of S-adenosylmethionine on the growth of human gastric cancer cells in vivo and in vitro - 0 views

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    SAMe show a decrease in gastric cell growth in vitro and in vivo studies. This appears to be secondary to the resolved hypomethylation status of the c-myc and the uPA genes.
Nathan Goodyear

High Glucose-Induced Expression of Proinflammatory Cytokine and Chemokine Genes in Monocytic Cells - 0 views

  • HG significantly increased the expression of monocyte chemoattractant protein-1 (MCP-1), TNF-α, β2-integrin, interleukin-1β, and others. HG treatment increased transcription of the MCP-1 gene, MCP-1 protein levels, and adhesion of THP-1 cells to endothelial cells. HG-induced MCP-1 mRNA expression and monocyte adhesion were blocked by specific inhibitors of oxidant stress, protein kinase C, ERK1/2, and p38 mitogen-activated protein kinases
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    High glucose associated with significant increase in inflammatory signaling.
Nathan Goodyear

Dynamic Regulation of Estrogen Receptor-β Expression by DNA Methylation During Prostate Cancer Development and Metastasis - 0 views

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    Methylation of the ER beta gene promoter region decreases ER beta expression and this has been associated with carcinogenesis of the prostate.
Nathan Goodyear

Cell - Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance through Wingless Signaling - 0 views

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    Sugar turns on cancer promoting genes Ras and Src.
Nathan Goodyear

Estrogen receptor ß genes associated with colorectal cancer mortality - 0 views

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    Additional support for ER beta role in protection in colon cancer.  This study found that SNPs in ER beta transcription resulted in reduced ER beta expression and a resultant increase in carcinogenesis.
Nathan Goodyear

Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis - 0 views

  • HIF-1 activation is highly associated with cancer cell growth and survival, tumor development, tumor angiogenesis, and poor clinical prognosis
  • The adaptation of cancer cells to hypoxia is mediated via hypoxia-inducible Factor 1 (HIF-1),1 a key transcription factor that up-regulates a series of genes involved in glycolytic energy metabolism, angiogenesis, cell survival, and erythropoiesis. Included among these genes are vascular endothelial growth factor (VEGF), erythropoietin (EPO), glucose transporters (GLUT), and several glycolytic enzymes (12, 13).
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    good discussion of HIF-1alpha and cancer
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