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Nathan Goodyear

Therapeutic hyperthermia: The old, the new, and the upcoming - Critical Reviews in Onco... - 1 views

www.croh-online.com/...fulltext

hyperthermia hyperthermic therapy cancer oncology

shared by Nathan Goodyear on 30 Aug 18 - No Cached
  • not well understood, but it is felt to be a combination of both heat-induced necrosis and of protein inactivation (e.g., repair enzymes) as opposed to DNA damage
  • alterations in tumor cytoskeletal and membrane structures, which disrupt cell motility and intracellular signal transduction
  • A common explanation for HT-enhancement of RT and CT involves inhibition of homologous recombination repair of double-strand DNA breaks, preventing cells from repairing sub-lethal damage
  • ...15 more annotations...
  • it does appear to inhibit rejoining of RT-induced DNA breaks more than is commonly observed after RT alone
  • HT damages cells and enhances RT and CT sensitivity as a function of both temperature and duration of treatment
  • as temperature or duration increase, the rate of cell killing also increases
  • At temperatures above 42 °C, tumor vasculature is damaged, resulting in decreased blood flow
  • Cancer cells are particularly vulnerable to heating; in vivo studies have shown that temperatures in the range of 40–44 °C cause more selective damage to tumor cells
  • cancerous blood vessels are chaotic, leaky, and inefficient
  • selective cytotoxic effect on tumor cells include inhibition of key cancer cell-signaling pathways such as AKT, inducing apoptosis, suppression of cancer stem cell proliferation, and others
  • increase in immunological attacks against tumors after HT, which were believed to be achieved through activation of HSPs and subsequent modulation of the innate and adaptive immune responses against tumor cells
  • HT does lead to activation of the immune system and HSP-induced cell death through modification of the tumor cell surface
  • These HSPs and tumor antigens are taken up by dendritic cells and macrophages and go on to induce specific anti-tumor immunity
  • In vivo studies demonstrate HT-enhancement of NK cell activity, and HT has been shown to increase neutrophilic granulocytes with anti-tumor activity
  • it has become increasingly clear that HT results in immune stimulation, through both direct heat-mediated cell killing as well as innate and adaptive immune system modulation
  • The term hyperthermia is used in this review to refer to heating within the clinically accepted range of 40–45 °C
  • temperatures above 42.5–43 °C the exposure time can be halved with each 1 °C increase while maintaining equivalent cell killing
  • gradual heating at 43 °C for 1 h worked through an apoptotic pathway
  • Nathan Goodyear on 30 Aug 18
     
    Comprehensive review of hyperthemic therapy.
Nathan Goodyear

Chemotherapy-Induced Metastasis: Molecular Mechanisms, Clinical Manifestations, Therape... - 0 views

www.ncbi.nlm.nih.gov/...PMC6744993

cancer cytokine storm metastasis chemotherapy

shared by Nathan Goodyear on 05 Apr 21 - No Cached
  • recent evidence has linked the cytotoxic effects of chemotherapy with the de novo elicitation of a prometastatic tumor microenvironment
  • Nathan Goodyear on 05 Apr 21
     
    Full dose chemotherapy induces cytokine storm to induce metastasis.
Nathan Goodyear

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC8924116

cancer NETosis SARS-CoV-2 COVID COVID-19 COVID19 platelets

shared by Nathan Goodyear on 18 Apr 23 - No Cached
  • Pneumonia is a typical symptom of COVID-19 infection, while acute respiratory distress syndrome (ARDS) and multiple organ failure are common in severe COVID-19 patients
  • NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage
  • SARS-CoV-2 infection has also been linked to increased neutrophil-to-lymphocyte ratios, which is associated with disease severity and clinical prognosis
  • ...40 more annotations...
  • NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Definition
  • increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis
  • Another indirect route of SARS-CoV-2-induced NET production is platelet activation
  • When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis
  • In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.
  • SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors
  • Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause
  • NETosis and NETs are increasingly recognized as causes of vascular injury
  • SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Connects SARS-CoV-2 to TLR on Platelets to NETosis to metastasis.
  • NET formation may be caused by activated platelets rather than SARS-CoV-2 itself
  • NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.
  • early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses
  • NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      NETosis-> tumor growth
  • NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation
  • “cytokine storm”
  • SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Cycle of hyperinflammation
  • NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response
  • patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]
  • COVID-19 NETs may act as potential inducers for autoimmune responses
  • have weakened adaptive immunity as well as a high level of inflammation
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Immunomodulation
  • tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised
  • NETs have also been shown to enhance macrophage pyroptosis in sepsis
  • facilitating an immunosuppressive microenvironment
  • persistent immunosuppression may result in bacterial co-infection or secondary infection
  • can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes
  • NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection
  • Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness
  • NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells
  • decreased E-cadherin (an epithelial marker) expression
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Leads to emt
  • COVID-19 also has a long-term influence on tumor progression
  • Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19
  • patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis
  • awaken cancer cells
  • NETs have been shown to change the tumor microenvironment
  • enhance tumor progression and metastasis
  • vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response
  • vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS
  • vitamin C may also inhibit NETosis and NET production in COVID-19
  • Metformin
  • Vitamin C
  • Nathan Goodyear on 18 Apr 23
     
    NETosis intimately involved in progressive COVID, long COVID, autoimmunity, and cancer
Nathan Goodyear

Selective Inhibition of L-Type Ca2+ Channels in A7r5 Cells by Physiological Levels of T... - 0 views

endo.endojournals.org/...2675

testosterone vasodilation calcium channel blocker cardiovascular CVD calcium channel blocker

shared by Nathan Goodyear on 14 May 13 - No Cached
  • Nathan Goodyear on 14 May 13
     
    Physiologic levels of testosterone shown to induce Calcium channel blockade.  This induces the beneficial cardiovascular vasodilation.  It is known that testosterone binds to the same receptor as the common calcium channel blocker nifedipine.
Nathan Goodyear

Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac rem... - 0 views

onlinelibrary.wiley.com/...abstract

T3 thyroid hormone hormones MI mitochondria HIF-1alpha

shared by Nathan Goodyear on 29 Jun 13 - No Cached
  • Nathan Goodyear on 29 Jun 13
     
    T3 in the post MI individual decreases the MI infarct size and the progression to heart failure. What is really  interesting about this study is that the T3 induced mitochondrial biogenesis and activity which is a great thing in recovery of MI and also in disease i.e. cancer.  However, it appears to increase HIF-1alpha and angiogenesis which is stimulated by retrograde signaling.  There is a muddied picture here.  Because T3 stimulates oxidative phosphorylation and mitochondria biogenesis which is favorable for health.  However, in this study of rats, it induced HIF-1alpha and angiogenesis in post MI, which is favorable to recovery, yet this is unfavorable for cancer.    Yet oxidative phosphorylation is favorable to cancer prevention/elimination and MI recovery.
Nathan Goodyear

Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fa... - 0 views

diabetes.diabetesjournals.org/...db07-1403

gut microbiota flora metabolic endotoxemia inflammation insulin resistance IR obesity diabetes DM

shared by Nathan Goodyear on 18 Jan 12 - No Cached
  • high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions
  • Nathan Goodyear on 18 Jan 12
     
    changes in the gut flora shown to induce metabolic endotoxemia, inflammation, insulin resistance, and obesity.  Granted, this study was done in mice.
Nathan Goodyear

Obesity - Inducible Toll-like Receptor and NF-[kappa]B Regulatory Pathway Expression in... - 0 views

www.nature.com/...oby200825a.html

TLR-4 TLR Toll-like receptors NF-kapppB inflammation obesity

shared by Nathan Goodyear on 19 Jan 12 - No Cached
  • TLRs are functionally inducible and associated with downstream NF-B activation and proinflammatory cytokine production.
  • TLRs represent a family of receptors that are critical to the innate immune response against foreign pathogens and microorganisms
  • LPS has been shown to induce proinflammatory chemokine gene expression in differentiated human adipocytes through TLR and NF-B action
  • ...2 more annotations...
  • Stimulation of TLRs initiates intracellular signaling cascades resulting in downstream NF-B and mitogen-activated protein kinase activation and production of proinflammatory chemokines associated with mechanisms of metabolic dysfunction and cardiovascular disease progression.
  • Elevated fatty acids levels associated with obesity activate TLR4 signaling in fat cells and macrophages, and induce insulin resistance in murine models
  • Nathan Goodyear on 19 Jan 12
     
    TLR, especially TLR-4, is directly involved in NF-KappaB activation and release of inflammatory cytokines
Nathan Goodyear

Nutrition Journal | Full text | Homocysteine and reactive oxygen species in metabolic s... - 0 views

www.nutritionj.com/4

homocysteine atherogenesis CVD metabolic syndrome metabolic syndrome

shared by Nathan Goodyear on 23 Jul 12 - No Cached
  • Nathan Goodyear on 23 Jul 12
     
    homocysteine contributes to atherogenesis and CVD via: increased ROS, induces endothelial dysfunction, increases platelete adhesion and thrombosis, increases smooth muscle cell proliferation, endothelial cell cytotoxicity, increases LDL oxidation, vasoconstriction, increased MCP-1 and IL-8, and induces endothelial HMG CoA reductase.
Nathan Goodyear

Aging and Luteinizing Hormone Effects on Reactive Oxygen Species Production and DNA Dam... - 0 views

www.biolreprod.org/...100.full

LH ROS reactive oxygen species oxidative stress testicles Testosterone male hormone hormones

shared by Nathan Goodyear on 04 Dec 13 - No Cached
  • Nathan Goodyear on 04 Dec 13
     
    Interesting rat model finds that stimulation of the leydig cells of the testis by LH induces ROS.  May be one of the mechanisms by which androgen therapy will induce long-term requirement for replacement.
Nathan Goodyear

Autoimmune (auto-inflammatory) syndrome induce... [Curr Med Chem. 2013] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23992328

Macrophagic myofasciitis vaccine vaccines vaccinations ASIA autoimmune syndromes induced by adjuvants autoimmune disease adjuvants

shared by Nathan Goodyear on 01 Oct 14 - No Cached
  • Nathan Goodyear on 01 Oct 14
     
    Animal proof of concept supports the thought that adjuvants in vaccines induce auto inflammatory diseases.
Nathan Goodyear

Low mercury concentrations cause oxidative stress and endothelial dysfunction in conduc... - 0 views

ajpheart.physiology.org/...H1033.long

Hg mercury hypertension NO ROS oxidative stress glutathione GHS cardiovascular disease heart

shared by Nathan Goodyear on 16 Sep 14 - No Cached
  • Nathan Goodyear on 16 Sep 14
     
    Hg induces vascular ROS through depletion of glutathione.  This study found that low dose, chronic Hg exposure induced ROS that resulted in vascular dysfunction i.e. hypertension.
Nathan Goodyear

PLOS ONE: Low Mercury Concentration Produces Vasoconstriction, Decreases Nitric Oxide B... - 0 views

www.plosone.org/...10.1371%2Fjournal.pone.0049005

Hg mercury NO RAS renin angiotensin system ROS hypertension oxidative stress vasoconstriction

shared by Nathan Goodyear on 16 Sep 14 - No Cached
  • Nathan Goodyear on 16 Sep 14
     
    Animal model found that low Hg decreased NO availability.  The result is vasoconstriction induced by ROS and hypertension. The hypertension is the result of an activation of the renin angiotensin system.  The importance here is that low Hg levels induced this change.
Nathan Goodyear

Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among p... - 0 views

www.ncbi.nlm.nih.gov/...PMC3271178

estrogen metabolites estrogen metabolites cancer hormones

shared by Nathan Goodyear on 04 Oct 15 - No Cached
  • While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol estrogens with one hydroxyl group methylated, have been hypothesized to lower risk of breast cancer.
  • Despite the estrogenic and genotoxic potential of many of the EM, we only observed a significantly increased breast cancer risk with one EM, 17-epiestriol, which has particularly strong estrogenic activity and binds to both ERα and ERβ with an affinity comparable to estradiol
  • We did not observe reduced risk for higher concentrations of 2-pathway EM relative to 16-pathway EM, nor did we observe a consistent benefit of higher concentrations of methylated catechol EM compared with catechol EM.
  • ...4 more annotations...
  • EM also can be genotoxic, but the individual EM vary in their ability to induce DNA damage
  • Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly via redox cycling and generation of reactive oxygen species
  • the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized 2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination and mutations
  • 2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative DNA damage (46). These catechols also induce neoplastic transformation in ER-cells, and thus act independently from the ER
  • Nathan Goodyear on 04 Oct 15
     
    Estrogen metabolites.
Nathan Goodyear

Drug-induced lupus erythematosus. [Autoimmunity. 2005] - PubMed result - 0 views

www.ncbi.nlm.nih.gov/...16373256

Lupus drug-induced

shared by Nathan Goodyear on 19 Feb 11 - No Cached
  • More than 80 drugs have been associated with DILE.
  • Nathan Goodyear on 19 Feb 11
     
    Drug induced Lupus
Nathan Goodyear

[Drug-induced lupus erythematosus and systemic lup... [Przegl Lek. 2007] - PubMed result - 0 views

www.ncbi.nlm.nih.gov/...18409355

drug induced lupus

shared by Nathan Goodyear on 19 Feb 11 - No Cached
  • Since that time over 80 medications are known to be responsible for development of the disease.
  • Nathan Goodyear on 19 Feb 11
     
    Drug-induced Lupus
Nathan Goodyear

Drug-induced lupus: an update. [Lupus. 2006] - PubMed result - 0 views

www.ncbi.nlm.nih.gov/...17153847

drug-induced lupus

shared by Nathan Goodyear on 19 Feb 11 - No Cached
  • DILE has been accepted as a side effect of therapy with over 80 drugs since its first description in association with sulfadiazine in 1945.
  • Nathan Goodyear on 19 Feb 11
     
    drug-induced Lupus found in > 80 drugs
Nathan Goodyear

Kent Holtorf: Long Term Weight Loss - More Than Will Power? - 0 views

www.huffingtonpost.com/...-weight-loss---m_b_192933.html

leptin reverse T3 weight loss

shared by Nathan Goodyear on 09 Mar 11 - No Cached
  • which is a major reason for the regaining of lost weight with dieting as well being the mechanism behind stress induced weight gain (it is not due to increased cortisol).
  • f greater than 10, it demonstrates there is a degree of leptin resistance contributing to an inability to lose weight
  • that it is difficult to lose weight with leptin resistance. High carbohydrate diets and in particular high-fructose corn syrup is shown to significantly increase leptin resistance and is a likely mechanism that high fructose corn syrup is associated with obesity
  • ...9 more annotations...
  • inactive thyroid hormone called thyroxine
  • it is problem inside the cell that the inactive T4 is not converted to T3 but rather to a mirror image of T3 called reverse T3. The reverse T3 has the opposite effect of T3, blocking the effects of T3 and lowering rather than increasing metabolism.
  • Studies are showing that stress and dieting (especially yo-yo dieting) can set this hormone into action as well as chronic illness such as diabetes, chronic fatigue syndrome and fibromyalgia.
  • As soon as the body senses a reduction in calories, the production of reverse T3 is stimulated to lower metabolism
  • With chronic dieting or stress, the body often stays in this "starvation mode" with elevated levels of reverse T3 and decreased levels of T3, which is a major reason for the regaining of lost weight with dieting as well being the mechanism behind stress induced weight gain (it is not due to increased cortisol).
  • which is a major reason for the regaining of lost weight with dieting as well being the mechanism behind stress induced weight gain (it is not due to increased cortisol).
  • which is a major reason for the regaining of lost weight with dieting as well being the mechanism behind stress induced weight gain (it is not due to increased cortisol).
  • Studies are showing that such standard testing will miss 80% of thyroid dysfunction
  • ree T3/reverse T3 ratio
  • Nathan Goodyear on 09 Mar 11
     
    Fantastic review by Dr. Holtorf on reverse T3, leptin, and weight loss
Nathan Goodyear

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a p... - 0 views

www.ncbi.nlm.nih.gov/...PMC1224653

IV vitamin C vitamin C intravenous alternative Intravenous vitamin C vitamin C cancer H2O2 ascorbic acid

shared by Nathan Goodyear on 26 Aug 14 - No Cached
  • Nathan Goodyear on 26 Aug 14
     
    IV vitamin C and IV vitamin C only can deliver levels to tumor cells that induce formation of H2O2 that then induces cell death.
Nathan Goodyear

Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxid... - 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

http://www.diabetologia-journal.org/files/Narendran.pdf - 0 views

www.diabetologia-journal.org/...Narendran.pdf

exercise inflammation growth hormone GH IGF-1 TNF-alpha IL-6 IL-1beta IL-1Ra interferon-gamma diabetes islet cells

shared by Nathan Goodyear on 28 Oct 14 - No Cached
  • Nathan Goodyear on 28 Oct 14
     
    Exercise is not just for calories out.  Exercise increases growth hormone, IGF-1, glucagon-like peptide 1, IL-6, and IL-1ra.  The effect is to GH increases beta islet cell mass and protects beta cell lines against IL-1beta, Interferon-gamma and TNF-alhpa induced apoptosis.  IL-6 increased production increases GLP-1 and IL-1ra which counters IL-1beta.  Interleukin-1beta induces islet cell apoptosis and thus IL-1ra counters this pro-inflammatory signal.
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