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Nathan Goodyear

Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect - 0 views

www.ncbi.nlm.nih.gov/...PMC3180189

cancer reverse warburg effect warburg effect NF-kapppB HIF-1alpha Cav-1 H2O2

shared by Nathan Goodyear on 12 Nov 14 - No Cached
  • reducing oxidative stress with powerful antioxidants, is an important strategy for cancer prevention, as it would suppress one of the key early initiating steps where DNA damage and tumor-stroma metabolic-coupling begins. This would prevent cancer cells from acting as metabolic “parasites
  • Oxidative stress in cancer-associated fibroblasts triggers autophagy and mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the “reverse Warburg effect.
  • Then, oxidative stress, in cancer-associated fibroblasts, triggers the activation of two main transcription factors, NFκB and HIF-1α, leading to the onset of inflammation, autophagy, mitophagy and aerobic glycolysis in the tumor microenvironment
  • ...38 more annotations...
  • oxidative stress and ROS, produced in cancer-associated fibroblasts, has a “bystander effect” on adjacent cancer cells, leading to DNA damage, genomic instability and aneuploidy, which appears to be driving tumor-stroma co-evolution
  • tumor cells produce and secrete hydrogen peroxide, thereby “fertilizing” the tumor microenvironment and driving the “reverse Warburg effect.”
  • This type of stromal metabolism then produces high-energy nutrients (lactate, ketones and glutamine), as well as recycled chemical building blocks (nucleotides, amino acids, fatty acids), to literally “feed” cancer cells
  • loss of stromal caveolin (Cav-1) is sufficient to drive mitochondrial dysfunction with increased glucose uptake in fibroblasts, mimicking the glycolytic phenotype of cancer-associated fibroblasts.
  • oxidative stress initiated in tumor cells is transferred to cancer-associated fibroblasts.
  • Then, cancer-associated fibroblasts show quantitative reductions in mitochondrial activity and compensatory increases in glucose uptake, as well as high ROS production
  • These findings may explain the prognostic value of a loss of stromal Cav-1 as a marker of a “lethal” tumor microenvironment
  • aerobic glycolysis takes place in cancer-associated fibroblasts, rather than in tumor cells, as previously suspected.
  • our results may also explain the “field effect” in cancer biology,5 as hydrogen peroxide secreted by cancer cells, and the propagation of ROS production, from cancer cells to fibroblasts, would create an increasing “mutagenic field” of ROS production, due to the resulting DNA damage
  • Interruption of this process, by addition of catalase (an enzyme that detoxifies hydrogen peroxide) to the tissue culture media, blocks ROS activity in cancer cells and leads to apoptotic cell death in cancer cells
  • In this new paradigm, cancer cells induce oxidative stress in neighboring cancer-associated fibroblasts
  • cancer-associated fibroblasts have the largest increases in glucose uptake
  • cancer cells secrete hydrogen peroxide, which induces ROS production in cancer-associated fibroblasts
  • Then, oxidative stress in cancer-associated fibroblast leads to decreases in functional mitochondrial activity, and a corresponding increase in glucose uptake, to fuel aerobic glycolysis
  • cancer cells show significant increases in mitochondrial activity, and decreases in glucose uptake
  • fibroblasts and cancer cells in co-culture become metabolically coupled, resulting in the development of a “symbiotic” or “parasitic” relationship.
  • cancer-associated fibroblasts undergo aerobic glycolysis (producing lactate), while cancer cells use oxidative mitochondrial metabolism.
  • We have previously shown that oxidative stress in cancer-associated fibroblasts drives a loss of stromal Cav-1, due to its destruction via autophagy/lysosomal degradation
  • a loss of stromal Cav-1 is sufficient to induce further oxidative stress, DNA damage and autophagy, essentially mimicking pseudo-hypoxia and driving mitochondrial dysfunction
  • loss of stromal Cav-1 is a powerful biomarker for identifying breast cancer patients with early tumor recurrence, lymph-node metastasis, drug-resistance and poor clinical outcome
  • this type of metabolism (aerobic glycolysis and autophagy in the tumor stroma) is characteristic of a lethal tumor micro-environment, as it fuels anabolic growth in cancer cells, via the production of high-energy nutrients (such as lactate, ketones and glutamine) and other chemical building blocks
  • the upstream tumor-initiating event appears to be the secretion of hydrogen peroxide
  • one such enzymatically-active protein anti-oxidant that may be of therapeutic use is catalase, as it detoxifies hydrogen peroxide to water
  • numerous studies show that “catalase therapy” in pre-clinical animal models is indeed sufficient to almost completely block tumor recurrence and metastasis
  • by eliminating oxidative stress in cancer cells and the tumor microenvironment,55 we may be able to effectively cut off the tumor's fuel supply, by blocking stromal autophagy and aerobic glycolysis
  • breast cancer patients show systemic evidence of increased oxidative stress and a decreased anti-oxidant defense, which increases with aging and tumor progression.68–70 Chemotherapy and radiation therapy then promote further oxidative stress.69 Unfortunately, “sub-lethal” doses of oxidative stress during cancer therapy may contribute to tumor recurrence and metastasis, via the activation of myofibroblasts.
  • a loss of stromal Cav-1 is associated with the increased expression of gene profiles associated with normal aging, oxidative stress, DNA damage, HIF1/hypoxia, NFκB/inflammation, glycolysis and mitochondrial dysfunction
  • cancer-associated fibroblasts show the largest increases in glucose uptake, while cancer cells show corresponding decreases in glucose uptake, under identical co-culture conditions
  • Thus, increased PET glucose avidity may actually be a surrogate marker for a loss of stromal Cav-1 in human tumors, allowing the rapid detection of a lethal tumor microenvironment.
  • it appears that astrocytes are actually the cell type responsible for the glucose avidity.
  • In the brain, astrocytes are glycolytic and undergo aerobic glycolysis. Thus, astrocytes take up and metabolically process glucose to lactate.7
  • Then, lactate is secreted via a mono-carboxylate transporter, namely MCT4. As a consequence, neurons use lactate as their preferred energy substrate
  • both astrocytes and cancer-associated fibroblasts express MCT4 (which extrudes lactate) and MCT4 is upregulated by oxidative stress in stromal fibroblasts.34
  • In accordance with the idea that cancer-associated fibroblasts take up the bulk of glucose, PET glucose avidity is also now routinely used to measure the extent of fibrosis in a number of human diseases, including interstitial pulmonary fibrosis, postsurgical scars, keloids, arthritis and a variety of collagen-vascular diseases.
  • PET glucose avidity and elevated serum inflammatory markers both correlate with poor prognosis in breast cancers.
  • PET signal over-estimates the actual anatomical size of the tumor, consistent with the idea that PET glucose avidity is really measuring fibrosis and inflammation in the tumor microenvironment.
  • human breast and lung cancer patients can be positively identified by examining their exhaled breath for the presence of hydrogen peroxide.
  • tumor cell production of hydrogen peroxide drives NFκB-activation in adjacent normal cells in culture6 and during metastasis,103 directly implicating the use of antioxidants, NFκB-inhibitors and anti-inflammatory agents, in the treatment of aggressive human cancers.
  • Nathan Goodyear on 12 Nov 14
     
    Good description of the communication between cancer cells and fibroblasts.  This theory is termed the "reverse Warburg effect".
Nathan Goodyear

Prognostic Impact of the Tumor Marker CA 15-3 in Patients With Breast Cancer and Bone Metastases Treated With Palliative Radiotherapy - 0 views

www.ncbi.nlm.nih.gov/...PMC5289136

breast cancer "CA 15-3"

shared by Nathan Goodyear on 25 Oct 18 - No Cached
  • Nathan Goodyear on 25 Oct 18
     
    CA 15-3 tumor marker for breast cancer has mixed results. This study found no significant association with performance status with CA 15-3, as well as LDH, ALP, and albumin.
Nathan Goodyear

Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer | British Journal of Cancer - 0 views

www.nature.com/...bjc2014207

PET scan PET_CT scan cancer breast

shared by Nathan Goodyear on 19 Mar 18 - No Cached
  • We have demonstrated that the majority of patients have a sizeable reduction in SUVmax from a single cycle of NAC with a mean change of −32.3%
  • This study, however, failed to show any predictive markers of response after one cycle of chemotherapy
  • These data therefore suggest that the main utility of FLT-PET as an imaging biomarker in early breast cancer is pre-chemotherapy, as a marker of proliferation, rather than in predicting pathological response after chemotherapy
  • ...2 more annotations...
  • In terms of the histological proliferation biomarker Ki-67, we have shown a good correlation with FLT-PET pre-chemotherapy. The best predictive marker of response in terms of pCR was baseline Ki-67
  • Our study has shown that baseline Ki-67 and FLT SUVmax is well correlated in keeping with FLT-PETs status as a proliferation biomarker, although Ki-67 had a better predictive ability in terms of pathological outcome
  • Nathan Goodyear on 19 Mar 18
     
    PET CT scan shown to be useful as a proliferation biomarker pre-chemo in breast cancer.
Nathan Goodyear

Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients - 0 views

www.ncbi.nlm.nih.gov/...PMC3751545

IV vitamin C dosing ascorbic acid inflammation disease cancer IV vitamin C intravenous vitamin C IV intravenous vitamin C vitamin C CRP therapy treatment alternative

shared by Nathan Goodyear on 26 Aug 14 - No Cached
  • Patients with higher tumor markers are likely to have higher tumor burden, higher oxidative stress and, therefore, are more likely to have lower post IVC plasma levels.
  • Our data also showed that cancer patients with metastasis tend to have lower post-IVC vitamin C levels than those without metastasis
  • Lower peak plasma concentrations are obtained in cancer patients than in healthy subjects. Cancer patients who are deficient in vitamin C prior to therapy tend to achieve lower plasma levels post infusion.
  • ...25 more annotations...
  • Patients with higher inflammation or tumor burdens, as measured by CRP levels or tumor antigen levels, tend to show lower peak plasma ascorbate levels after IVC.
  • Patients with metastatic tumors tend to achieve lower post infusion plasma ascorbate levels than those with localized tumors.
  • Meta-analyses of clinical studies involving cancer and vitamins also conclude that antioxidant supplementation does not interfere with the efficacy of chemotherapeutic regiments
  • Most of the prostate cancer patients studied, 75±19% (95% confidence), showed reductions in PSA levels during the course of their IVC therapy
  • Laboratory studies suggest that, at high concentrations, ascorbate does not interfere with chemotherapy or irradiation and may enhance efficacy in some situations
  • Cameron and Pauling observed fourfold survival times in terminal cancer patients treated with intravenous ascorbate infusions followed by oral supplementation
  • The inflammatory microenvironment of cancer cells leads to increasing oxidative stress, which apparently depletes vitamin C, resulting in lower plasma ascorbate concentrations in blood samples post IVC infusion. Another explanation for this finding may be that cancers are themselves more metabolically active in their uptake of vitamin C, causing subjects to absorb more of the vitamin, and as a results show lower plasma ascorbate concentrations in blood post IVC infusion.
  • patients with severely elevated CRP levels attain plasma ascorbate concentrations after IVC infusions that are only 65% of those attained for subjects with normal CRP levels
  • The finding of decreased plasma ascorbate levels in cancer patients may relate to the molecular structure of ascorbic acid; in particular, the similarity of its oxidized form, dihydroascorbic acid, to glucose
  • Since tumor have increased requirement for glucose [67], transport of dehydroascorbate into the cancer cells via glucose transport molecules and ascorbate through sodium-dependent transporter may be elevated
  • Increased accumulation of ascorbic acid in the tumor site was supported by measurements of the level of ascorbic acid in tumors in animal experiments
  • patients with advanced malignancies may have lower level of ascorbic acid in tissue, creating a higher demand for the vitamin C
  • IVC therapy appears to reduce CRP levels in cancer patients.
  • CRP concentrations directly correlate with disease activity in many cases and can contribute to disease progression through a range of pro-inflammatory properties.
  • Being an exquisitely sensitive marker of systemic inflammation and tissue damage, CRP is very useful in screening for organic disease and monitoring treatment responses
  • ncreases in CRP concentrations have been associated with poorer prognosis of survival in cancer patients, particularly with advance disease independent of tumor stage
  • Regarding inflammation, 73±13% of subjects (95% confidence) showed a reduction in CRP levels during therapy. This was an even more dramatic 86±13% (95% confidence) in subjects who started therapy with CRP levels above 10 mg/L
  • patients treated by IVC with follow-up several year showed that suppression of inflammation in cancer patients by high-dose IVC is feasible and potentially beneficial
  • Inflammation is a marker of high cancer risk, and poor treatment outcome
  • The subjects with highly elevated CRP concentrations have a three-fold elevation “all-cause” mortality risk and a twenty-eight fold increase in cancer mortality risk
  • cancer patients may need higher doses to achieve a given plasma concentration.
  • patients with lower vitamin C levels may see more distribution of intravenously administered ascorbate into tissues and thus attain less in plasma.
  • When treating patients with IVC, the first treatment likely serves to replenish depleted tissue stores, if those subjects were vitamin C deficient at the beginning of the treatment. Then, in subsequent treatments, with increasing doses, higher plasma concentrations can be attained. On-going treatments serve to progressively reduce oxidative stress in cancer patients.
  • large doses given intravenously may result in maximum plasma concentrations of roughly 30 mM, a level that has been shown to be sufficient for preferential cytotoxicity against cancer cells
  • oral intake of vitamin C exceeded 200 mg administered once daily, it was difficult to increase plasma and tissue concentrations above roughly 200 μM.
  • Nathan Goodyear on 26 Aug 14
     
    Great review on the use of IV vitamin C in cancer and to reduce inflammation.  The article does a great job of discussing the mechanism of vitamin C therapy in cancer as well as the proposed reasons for low vitamin C in cancer patients.  The study also highlights the obstacles to rise in vitamin C levels post IV vitamin C in cancer patients.
Nathan Goodyear

[Malondialdehyde (MDA) as a lipid peroxidation marker]. - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...15765761

MDA malondialdehyde oxidative stress peroxidation free radicals

shared by Nathan Goodyear on 05 Dec 17 - No Cached
  • Nathan Goodyear on 05 Dec 17
     
    Only abstract her and it is an older article.  Malondialdehyde (MDA) is a great marker of oxidative stress.  Specifically, MDA is an end product of polyunsaturated fat peroxidation.
Nathan Goodyear

IL-1α and IL-1β Levels in Blood Serum and Saliva ... [Endocr Res. 2012] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...22894561

biomarkers interleukins IL-1Beta IL-1alpha saliva salivary inflammation

shared by Nathan Goodyear on 05 Nov 12 - No Cached
  • Nathan Goodyear on 05 Nov 12
     
    Interleukins IL-1alpha and IL-1beta in saliva found to not be signifcantly different than serum.  Point: saliva is a good medium to evaluate many other biomarkers, inflammatory markers in this case.
Nathan Goodyear

Journal of Endocrinological Investigation - 0 views

www.jendocrinolinvest.it/...abstract.cfm

thyroid cancer thyroid nodules nodules TSH autoimmune TPO anti-thyroglobulin antibodies

shared by Nathan Goodyear on 28 May 13 - No Cached
  • Nathan Goodyear on 28 May 13
     
    elevated autoimmune markers against the thyroid and an elevated TSH are both independent risk factors for thyroid malignancy in those with thyroid nodules.
Nathan Goodyear

Effect of Arnica D30 in marathon runners. Pooled ... [Homeopathy. 2003] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...14587684

marathon runners homeopathy arnica muscle soreness

shared by Nathan Goodyear on 01 Jun 13 - No Cached
  • Nathan Goodyear on 01 Jun 13
     
    Arnica found to lower muscle soreness after marathons, but not found to lower cell damage markers.
Nathan Goodyear

Study Finds High-dose Intravenous Vitamin C Reduces Pain and Inflammation in Those... -- WICHITA, Kan., Dec. 5, 2012 /PRNewswire-USNewswire/ -- - 0 views

www.prnewswire.com/...inic-scientists-182195661.html

pain inflammation RA rheumatoid arthritis arthritis IV IV vitamin C vitamin C Intravenous vitamin C

shared by Nathan Goodyear on 02 Jun 13 - No Cached
  • Nathan Goodyear on 02 Jun 13
     
    High dose IV vitamin C shown to reduce both pain and inflammation in patients with RA.  This study looked at doses only up to 50 grams.  The specific inflammatory marker that this study looked at was CRP and it was reduced on average by 44%.
Nathan Goodyear

JTM | Full text | Effect of high-dose intravenous vitamin C on inflammation in cancer patients - 0 views

www.translational-medicine.com/...189

inflammation cancer IV vitamin C intravenous vitamin C vitamin C vitamin C

shared by Nathan Goodyear on 02 Jun 13 - No Cached
  • Nathan Goodyear on 02 Jun 13
     
    high dose IV vitamin C shown to reduce inflammatory and tumor markers in cancer patients.
Nathan Goodyear

Effect of systemic vitamin C on free fatty ac... [Diabetes Metab. 2004] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...15671911

vitamin C lipid peroxidation antioxidant vitamin

shared by Nathan Goodyear on 05 Jun 13 - No Cached
  • Nathan Goodyear on 05 Jun 13
     
    Vitamin C shown to improve endothelial function, but not shown to decrease lipid peroxidation marker.
Nathan Goodyear

Co-occurrence of Cardiovascular and Prothrombotic Risk Facto... : Obstetrics & Gynecology - 0 views

journals.lww.com/...ular_and_Prothrombotic.16.aspx

preeclampsia CVD cardiovascular disease cardiovascular disease obstetrics

shared by Nathan Goodyear on 21 Dec 12 - No Cached
  • Nathan Goodyear on 21 Dec 12
     
    preeclampsia should be a history marker that reveals increased cardiovascular disease (CVD).  
Nathan Goodyear

Progesterone and estrogen receptors in meningiom... [J Neurosurg. 1997] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...8988089

meningioma progesterone receptor PR estrogen receptors ER

shared by Nathan Goodyear on 05 Feb 13 - No Cached
  • Nathan Goodyear on 05 Feb 13
     
    This study found that the presence of progesterone receptors was a favorable marker for those with meningioma's.  Only, a small number of estrogen receptors were found.  This study was from 1997.  
Nathan Goodyear

Roundup Disrupted Male Reproductive Func... [Free Radic Biol Med. 2013] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23820267

roundup infertility male glyphosate glutathione

shared by Nathan Goodyear on 04 Jul 13 - No Cached
  • Nathan Goodyear on 04 Jul 13
     
    Glyphosate, component of Roundup is well known to be an endocrine disruptor.  This rat study describes the mechanism  of disruption of the Sertoli cells resulting in male infertility.  In addition to the disruption of spermatogenesis, Glyphosate was shown to deplete glutathione levels compromising detoxification.  If that is not enough, oxidative damage marker TBARS was elevated.  
Nathan Goodyear

Chronic Subclinical Inflammation as Part of the Insulin Resistance Syndrome - 0 views

circ.ahajournals.org/...42.full

inflammation insulin resistance CRP fibrinogen

shared by Nathan Goodyear on 17 Oct 12 - No Cached
  • Nathan Goodyear on 17 Oct 12
     
    All 3 inflammatory markers used in this study (CRP, fibrinogen, wbc)  all correlated with insulin resistance
Nathan Goodyear

Endogenous Estrogens Influence Endothelial Function in Young Men - 0 views

circres.ahajournals.org/...1127.long

aromatase inhibition anastrozole arimidex men

shared by Nathan Goodyear on 25 Apr 12 - No Cached
  • Nathan Goodyear on 25 Apr 12
     
    aromatase inhibition with anastrozole, in this study, resulted in impaired flow mediated dilation.  No resultant change in inflammatory markers were seen.  Again, my problem with this study is the use of serum for the hormone evaluation.  I would bet not enough aromatase inhibition was provided.
Nathan Goodyear

The origins of age-related proinflammatory state - 0 views

bloodjournal.hematologylibrary.org/...2294.full

inflammation aging cytokines immune system adipocytokines

shared by Nathan Goodyear on 25 Apr 12 - No Cached
  • Nathan Goodyear on 25 Apr 12
     
    aging found to be associated with a rise in inflammatory markers.  This leads to the theory that age-related diseases are in part due to chronic inflammation
Nathan Goodyear

Estradiol and inflammatory markers in Older Men - 0 views

jcem.endojournals.org/...518.full.pdf

Estradiol inflammation inflammatory cytokines IL-6 CRP men hormone hormones

shared by Nathan Goodyear on 29 Apr 12 - No Cached
  • Nathan Goodyear on 29 Apr 12
     
    In this study, estradiol is associate with increased IL-6 in elderly men. No correlation was seen with TNFalpha, and CRP.
Nathan Goodyear

Reduction of Inflammatory Cytokine Concentrations and Improvement of Endothelial Functions in Obese Women After Weight Loss Over One Year - 0 views

circ.ahajournals.org/...804

obesity overweight visceral adiposity adipose tissue cytokines adipocytokines TNF-alpha IL-6 P-selectin ICAM-1 VCAM-1 CVD cardiovascular disease weight loss weight loss

shared by Nathan Goodyear on 30 Mar 12 - No Cached
  • Nathan Goodyear on 30 Mar 12
     
    adipose tissue releases inflammatory markers (cytokines IL-6, TNF-alpha, V-CAM-1, ICAM-1, and P-selectin). Associated endovascular disfunction and eventually cardiovascular disease.  A direct link between obesity induced inflammation and endovascular dysfunction.  Weight loss in these obese women reduced secretion of the associated inflammatory cytokines and thus decreased vascular dysfunction.
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