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Nathan Goodyear

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

www.pnas.org/...13604.full

IV vitamin C cancer ascorbic acid vitamin C H2O2 GPX glutathione Perioxidase

shared by Nathan Goodyear on 09 Feb 11 - Cached
  • Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues.
  • These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial
  • pharmacologic concentrations of ascorbate killed cancer but not normal cells, that cell death was dependent only on extracellular but not intracellular ascorbate, and that killing was dependent on extracellular hydrogen peroxide (H2O2) formation with ascorbate radical as an intermediate
  • ...48 more annotations...
  • Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration
  • Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid
  • ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu
  • H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents
  • The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      The mechansism here is inadequate recycling of GSH due to lack of G6PD, build up of intracellular H2O2 and RBC lysis--hemolysis.
  • Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate
  • Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration
  • Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations
  • For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      accumulation of extracellular vitamin C is the effect.
  • It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.
  • There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.
  • H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections
  • Neutrophils generate H2O2 from superoxide,
  • i.v. ascorbate is effective in some viral infections
  • H2O2 is toxic to hepatitis C
  • Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.
  • Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose
  • As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,
  • Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm
  • Human Burkitt's lymphoma cells
  • We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines
  • Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration
  • plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption
  • For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion
  • All tested normal cells were insensitive to 20 mM ascorbate.
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      meaning safe.
  • Lymphoma cells were selected because of their sensitivity to ascorbate
  • As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death
  • Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      work continued beyond the IVC therapy itself
  • In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate
  • Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate
  • Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.
  • extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.
  • H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death
  • Superoxide dismutase was not protective
  • Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate
  • For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased
  • Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes
  • There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity
  • H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media
  • ascorbate radical is a surrogate marker for H2O2 formation.
  • whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable
  • The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.
  • The occurrence of one predicted complication, oxalate kidney stones, is controversial
  • In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis
  • ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.
  • ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation
  • data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      the conversion of ascorbate to H2O2 occurs extracellular
  • More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis
  • Nathan Goodyear on 09 Feb 11
     
    IV vitamin C benefits cancer patients
fitspresso

https://www.sightcare-co.com/ - 0 views

www.sightcare-co.com

sight care sightcare group training nearsightedness food for eyesight carey codd vitasight vision how to cure bad eye tips fix improve your red light eyes diet improvement skincare malaysia costos de medicare indonesia singapore eyecare

shared by fitspresso on 27 Sep 23 - No Cached
  • fitspresso on 27 Sep 23
     
    Sight Care | Official Site sightcare-co.com · by Sight Care Sight Care Only $49/Bottle Limited Time Offer! Sight Care Special Deal + Special 67% Discount Save $600 + 180 Days Money Back Guarantee #1.The Sight Care vision supplement is a dietary supplement for helping you improve your vision and brain health. Sight Care eye supplements are formulated to provide a synergistic blend of vitamins, minerals, antioxidants, and other bioactive compounds that are essential for maintaining healthy vision Regular Price: 147/per bottle Only for: $49/per bottle What Is Sight Care? This powerful vision support supplement is made with a unique blend of natural ingredients and plant extracts that work together synergistically to deliver numerous benefits for your brain and eye health. With Sight Care, you can expect to experience increased energy levels, improved eyesight, and an overall revitalized sense of well-being. Taking care of your vision health is not just about seeing clearly; it's also about maintaining your overall brain health. As we age, our vision deteriorates, and our eyes and brain can experience a decline in function, but there are steps you can take to support your visual and cognitive health. Regular eye exams are crucial for detecting and treating vision problems early on, and making healthy choices such as eating a nutritious diet and exercising regularly can also help. However, with busy schedules, it can be difficult to find the time to devote to a healthy lifestyle. This is where the Sight Care supplement comes in. It's designed to support both vision and brain health with its blend of natural ingredients that have been shown to promote healthy vision and cognitive function You must not compromise your eye health for momentary exhilaration. If you are glued to digital screens day and night, you must take measures to prevent eye diseases like age-related macular degeneration. The SightCare vision supplement has been made using 100% natura
Nathan Goodyear

Intravenous Ascorbate as a Tumor Cytotoxic Chemotherapeutic Agent - 0 views

www.seanet.com/...d_hypotheses_1995-v44-p207.htm

vitamin C cancer IV vitamin C ascorbic acid

shared by Nathan Goodyear on 05 Mar 18 - No Cached
  • There is a 10 — 100-fold greater content of catalase in normal cells than in tumor cells
  • induce hydrogen peroxide generation
  • Ascorbic acid and its salts (AA) are preferentially toxic to tumor cells in vitro (6 — 13) and in vivo
  • ...36 more annotations...
  • related to intracellular hydrogen peroxide generation
  • only be obtained by intravenous administration of AA
  • Preferentially kills neoplastic cells
  • Is virtually non-toxic at any dosage
  • Does not suppress the immune system, unlike most chemotherapy agents
  • Increases animal and human resistance to infectious agents by enhancing lymphocyte blastogenesis, enhancing cellular immunity, strengthening the extracellular matrix, and enhancing bactericidal activity of neutrophils and modulation of complement protein
  • Strengthens the structural integrity of the extracellular matrix which is responsible for stromal resistance to malignant invasiveness
  • 1969, researchers at the NCI reported AA was highly toxic to Ehrlich ascites cells in vitro
  • In 1977, Bram et al reported preferential AA toxicity for several malignant melanoma cell lines, including four human-derived lines
  • Noto et al reported that AA plus vitamin K3 had growth inhibiting action against three human tumor cell lines at non-toxic levels
  • Metabolites of AA have also shown antitumor activity in vitro
  • The AA begins to reduce cell proliferation in the tumor cell line at the lowest concentration, 1.76 mg/dl, and is completely cytotoxic to the cells at 7.04 mg/dl
  • the normal cells grew at an enhanced rate at the low dosages (1.76 and 3.52 mg/dl)
  • preferential toxicity of AA for tumor cells. >95% toxicity to human endometrial adenocarcinoma and pancreatic tumor cells (ATCC AN3-CA and MIA PaCa-2) occurred at 20 and 30 mg/dl, respectively.
  • No toxicity or inhibition was demonstrated in the normal, human skin fibroblasts (ATCC CCD 25SK) even at the highest concentration of 50 mg/dl.
  • the use of very high-dose intravenous AA for the treatment of cancer was proposed as early as 1971
  • Cameron and Pauling have published extensive suggestive evidence for prolonged life in terminal cancer patients orally supplemented (with and without initial intravenous AA therapy) with 10 g/day of AA
  • AA, plasma levels during infusion were not monitored,
  • the long-term, oral dosage used in those experiments (10 g/day), while substantial and capable of producing immunostimulatory and extracellular matrix modulation effects, was not high enough to achieve plasma concentrations that are generally cytotoxic to tumor cells in culture
  • This low cytotoxic level of AA is exceedingly rare
  • 5 — 40 mg/dl of AA is required in vitro to kill 100% of tumor cells within 3 days. The 100% kill levels of 30 mg/dl for the endometrial carcinoma cells and 40 mg/dl for the pancreatic carcinoma cells in Figure 2 are typical
  • normal range (95% range) of 0.39-1.13 mg/dl
  • 1 h after beginning his first 8-h infusion of 115 g AA (Merit Pharmaceuticals, Los Angeles, CA), the plasma AA was 3.7 mg/dl and at 5 h was 19 mg/dl. During his fourth 8-h infusion, 8 days later, the 1 h plasma level was 158 mg/dl and 5 h was 185 mg/dl
  • plasma levels of over 100 mg/dl have been maintained in 3 patients for more than 5 h using continuous intravenous infusion
  • In rare instances of patients with widely disseminated and rapidly proliferating tumors, intravenous AA administration (10 — 45 g/day) precipitated widespread tumor hemorrhage and necrosis, resulting in death
  • Although the outcomes were disastrous in these cases, they are similar to the description of tumor-necrosis-factor-induced hemorrhage and necrosis in mice (52) and seem to demonstrate the ability of AA to kill tumor cells in vivo.
  • toxic effects of AA on one normal cell line were observed at 58.36 mg/dl and the lack of side effects in patients maintaining >100 mg/dl plasma levels
  • Although it is very rare, tumor necrosis, hemorrhage, and subsequent death should be the highest priority concern for the safety of intravenous AA for cancer patients.
  • Klenner, who reported no ill effects of dosages as high as 150 g intravenously over a 24-h period
  • Cathcart (55) who describes no ill effects with doses of up to 200 g/d in patients with various pathological conditions
  • following circumstances: renal insufficiency, chronic hemodialysis patients, unusual forms of iron overload, and oxalate stone formers
  • Screening for red cell glucose-6-phosphate dehydrogenase deficiency, which can give rise to hemolysis of red blood cells under oxidative stress (57), should also be performed
  • any cancer therapy should be started at a low dosage to ensure that tumor hemorrhage does not occur.
  • patient is orally supplementing between infusions
  • a scorbutic rebound effect can be avoided with oral supplementation. Because of the possibility of a rebound effect, measurement of plasma levels during the periods between infusions should be performed to ensure that no such effect takes place
  • Every effort should be made to monitor plasma AA levels when a patient discontinues intravenous AA therapy.
  • Nathan Goodyear on 05 Mar 18
     
    Older study, 1995, but shows the long-standing evidence that IVC preferentially is cytotoxic to cancer cells.`
Nathan Goodyear

High-Dose Vitamin C for Cancer Therapy - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC9231292

vitamin C cancer

shared by Nathan Goodyear on 27 Jul 22 - No Cached
  • diabetes [8], atherosclerosis [9], the common cold [10], cataracts [11], glaucoma [12], macular degeneration [13], stroke [14], heart disease [15], COVID-19 [16], and cancer.
  • 1–5% of the Vit-C inside the human cells
  • interaction between Fe(II) and H2O2 produces OH− through the Fenton reaction
  • ...35 more annotations...
  • metabolic activity, oxygen transport, and DNA synthesis
  • Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.
  • macrophages contain considerable quantities of iron
  • iron is taken up by the majority of cells in the form of a transferrin (Tf)-Fe(III) complex that binds to the cell surface receptor transferrin receptor 1 (TfR1)
  • excess iron is retained in the liver cells
  • the endosomal six transmembrane epithelial antigen of the prostate 3 (STEAP3) reduces Fe(III) (ferric ion) to Fe(II) (ferrous ion), which is subsequently transferred across the endosomal membrane by divalent metal transporter 1 (DMT1)
  • labile iron pool (LIP)
  • LIP is toxic to the cells owing to the production of massive amounts of ROS.
  • DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH
  • Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)
  • Ascorbate can efficiently reduce free iron, thus recycling the cellular Fe(II)/Fe(III) to produce more OH• from H2O2 than can be generated during the Fenton reaction, which ultimately leads to lipid, protein, and DNA oxidation
  • Vit-C-stimulated iron absorption
  • reduce cellular iron efflux
  • high-dose Vit-C may elevate cellular LIP concentrations
  • ascorbate enhanced cancer cell LIP specifically by generating H2O2
  • Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately
  • tumor cells have a need for readily available Fe(II) to survive and proliferate.
  • Tf has been recognized to sequester most labile Fe(II) in vivo
  • Asc•− and H2O2 were generated in vivo upon i.v Vit-C administration of around 0.5 g/kg of body weight and that the generation was Vit-C-dose reliant
  • free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production
  • iron metabolism is altered in malignancies
  • increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways
  • Fe(II) ion in breast cancer cells is almost double that in normal breast tissues
  • macrophages in the cancer microenvironment have been revealed to increase iron shedding
  • Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease
  • increased the amount of LIP inside the cells through transferrin receptor (TfR)
  • Warburg effect, or metabolic reprogramming,
  • Warburg effect is aided by KRAS or BRAF mutations
  • Vit-C is supplied, it oxidizes to DHA, and then is readily transported by GLUT-1 in mutant cells of KRAS or BRAF competing with glucose [46]. DHA is quickly converted into ascorbate inside the cell by NADPH and GSH [46,107]. This decrease reduces the concentration of cytosolic antioxidants and raises the intracellular ROS amounts
  • increased ROS inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
  • ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+ (a critical co-factor of GAPDH); thus, further reducing the GAPDH associated with a multifaceted metabolic rewiring
  • Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
  • high-dose Vit-C recruited metabolites and increased the enzymatic activity in the pentose phosphate pathway (PPP), blocked the tri-carboxylic acid (TCA) cycle, and increased oxygen uptake, disrupting the intracellular metabolic balance and resulting in irreversible cell death, due to an energy crisis
  • mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2
  • Due to its great volatility at neutral pH [76], bolus therapy with mega-dose DHA has only transitory effects on tumor cells, both in vitro and in vivo.
Nathan Goodyear

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC4537815

cancer pancreatic cancer IV vitamin C vitamin c radiation

shared by Nathan Goodyear on 30 Jan 18 - No Cached
  • Previous studies from our laboratory have demonstrated that pharmacological ascorbate is cytotoxic to pancreatic cancer cells while normal cells are resistant
  • Ascorbate-induced cytotoxicity is mediated by the formation of H2O2 during the oxidation of ascorbate
  • the combination of IR + ascorbate increased the concentration of intracellular H2O2
  • ...17 more annotations...
  • Under steady-state conditions, intracellular GSH is maintained at millimolar concentrations, which keeps cells in a reduced environment and serves as the principal intracellular redox buffer when cells are subjected to an oxidative stressor including H2O2 (26). Glutathione peroxidase (GPx) activity catalyzes the reduction of H2O2 to water with the conversion of GSH to glutathione disulfide (GSSG). Under steady-state conditions, GSSG is recycled back to GSH by glutathione disulfide reductase using reducing equivalents from NADPH. However, under conditions of increased H2O2 flux, this recycling mechanism may become overwhelmed leading to a depletion of intracellular GSH (27, 28).
  • ascorbate radiosensitization can create an overwhelming oxidative stress to pancreatic cancer cells resulting in oxidation/depletion of the GSH intracellular redox buffer, resulting in cell death.
  • Treatment with the combination of ascorbate + IR significantly delayed tumor growth compared to controls or ascorbate alone
  • Ascorbate + IR also significantly increased overall survival compared to controls, IR alone or ascorbate alone
  • 54% of mice treated with the combination of IR + ascorbate had no measurable tumors
  • Glutathione is a measurable marker indicative of the oxidation state of the thiol redox buffer in cells. In severe systemic oxidative stress, the GSSG/2GSH couple may become oxidized, i.e. the concentration of GSH decreases and GSSG may increase because the capacity to recycle GSSG to GSH becomes rate-limiting
  • This suggests that the very high levels of pharmacological ascorbate in these experiments may have a pro-oxidant toward red blood cells as seen by a decrease in the capacity of the intracellular redox buffer
  • These data support the hypothesis that ascorbate radiosensitization does not cause an increase in oxidative damage from lipid-derived aldehydes to other organs.
  • Our current study demonstrates the potential for pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
  • pharmacological ascorbate enhances IR-induced cell killing and DNA fragmentation leading to induction of apoptosis in HL60 leukemia cells
  • pharmacological ascorbate significantly decreases clonogenic survival and inhibits the growth of all pancreatic cancer cell lines as a single agent, as well as sensitizes cancer cells to IR
  • Hurst et al. demonstrated that pharmacological ascorbate combined with IR leads to increased numbers of double-strand DNA breaks and cell cycle arrest when compared to either treatment alone
  • pharmacological ascorbate could serve as a “pro-drug” for the delivery of H2O2 to tumors
  • the double-strand breaks induced by H2O2 were more slowly repaired
  • The combination of ascorbate and IR provide two distinct mechanisms of action: ascorbate-induced toxicity due to extracellular production of H2O2 that then diffuses into cells and causes damage to DNA, protein, and lipids; and radiation-induced toxicity as a result of ROS-induced damage to DNA. In addition, redox metal metals like Fe2+ may play an important role in ascorbate-induced cytotoxicity. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of H2O2; labile iron can also react with H2O2. Recently our group has demonstrated that pharmacological ascorbate and IR increase the labile iron in tumor homogenates from this murine model of pancreatic cancer
  • we demonstrated that ascorbate or IR alone decreased tumor growth, but the combination treatment further inhibited tumor growth, indicating that pharmacological ascorbate is an effective radiosensitizer in vivo
  • data suggest that pharmacological ascorbate may protect the gut locally by decreasing IR-induced damage to the crypt cells, and systemically, by ameliorating increases in TNF-α
  • Nathan Goodyear on 30 Jan 18
     
    IV vitamin C effective as radiosensitizer in pancreatic cancer.
Nathan Goodyear

The permeability of the human red cell ... [Biochim Biophys Acta. 1994] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...7918566

sex hormones BHRT RBC red blood cells saliva salivary hormone serum transdermal

shared by Nathan Goodyear on 28 Nov 11 - No Cached
  • Nathan Goodyear on 28 Nov 11
     
    sex hormones readily carried on human red blood cells.  Reason transdermal progesterone is picked up in saliva and not serum.  Sex hormones are lipophillic and blood is water soluble.
Nathan Goodyear

Anemia in cancer - 0 views

annonc.oxfordjournals.org/...vii167.long

cancer anemia

shared by Nathan Goodyear on 30 Mar 15 - No Cached
  • Anemia is a frequent finding in cancer patients, occurring in >40% of cases
  • chemotherapy, the incidence of anemia may rise to 90%
  • Anemia exerts a negative influence on the quality of life
  • ...17 more annotations...
  • Anemia has also been identified as an adverse prognostic factor
  • mild (10 g/dl—normal), moderate (8–10 g/dl), severe (6.5–8 g/dl) and life threatening (<6.5 g/dl or unstable patient) anemia
  • anemia in cancer patients is often multifactorial.
  • Cancer itself can directly cause or exacerbate anemia either by suppressing hematopoiesis through bone marrow infiltration or production of cytokines that lead to iron sequestration, or by reduced red blood cell production
  • in inflammatory anemia, iron deficiency should be defined by a low transferrin saturation of <20%, ferritin levels of <100 ng/ml and a low reticulocyte hemoglobin concentration of <32 pg
  • anemia to thrombocytosis, as commonly seen in cancer patients
  • TNF-α inhibits hemoglobin production
  • Numerous in vitro studies have illustrated the central role of TNF-α in the pathogenesis of anemia
  • Other cytokines, such as interleukin-6 (IL-6), IL-1 and interferon-γ, have also been shown to inhibit erythroid precursors in vitro [9], albeit to a lesser extent
  • In inflammation, from whatever cause, IL-6 induces the liver to produce hepcidin. Hepcidin decreases iron absorption from the bowel and blocks iron utilization in the bone marrow
  • treatment itself may be a major cause of anemia
  • nephrotoxic effects of particular cytotoxic agents such as platinum salts can also lead to the persistence of anemia through reduced Epo production by the kidney
  • Currently two options are at the disposal of the clinician for the treatment of anemia in cancer patients: transfusion of packed red blood cells and the use of erythropoiesis-stimulating agents (ESAs)
  • The goal of the treatment is to relieve the symptoms of anemia such as fatigue and dyspnea.
  • Transfusion of 1 unit of packed red blood cells has been estimated to result in an increase in the hemoglobin level of 1 g/dl in a normal-sized adult
  • a higher mortality rate in patients receiving ESA treatment
  • Recent concerns regarding the risk of thromboembolism in patients treated with ESA have been corroborated by the meta-analyses conducted by Tonnelli and Bennett
  • Nathan Goodyear on 30 Mar 15
     
    Great review of anemia in Cancer:  1)  blood loss 2)  increased RBC loss 3)   decreased RBC production Cancer infiltration of marrow can reduce hematopoiesis.  Inflammatory cytokines can reduce hematopoiesis.  Inflammatory cytokines can block Fe absorption.  Chemo and radiation can cause anemia--particularily platinum based therapies.
Nathan Goodyear

Broad targeting of angiogenesis for cancer prevention and therapy - 0 views

www.ncbi.nlm.nih.gov/...PMC4737670

cancer curcumin VEGF EGCG green tea melatonin quercetin Resveratrol silymarin flavonoids HIF-1alpha

shared by Nathan Goodyear on 01 Jun 18 - No Cached
  • vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), interleukin-8 (IL-8), placental growth factor (PlGF), transforming growth factor-beta (TGFbeta), platelet derived growth factor (PDGF), angiopoietins (Angs) and others (reviewed in [4])
  • The switch may also involve down-regulation of endogenous inhibitors of angiogenesis such as endostatin, angiostatin or thrombospondin (reviewed in [5]) and has thus been regarded as the result of tipping the net balance between positive and negative regulators
  • There is a complex interrelationship between tumor hypoxia and tumor angiogenesis
  • ...17 more annotations...
  • chronic hypoxia
  • acute hypoxia
  • Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth
  • HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)
  • When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways
  • c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.
  • mTOR can also promote stabilization and HIF transcriptional activity
  • hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment
  • Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration
  • Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments
  • The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group
  • Resveratrol inhibits capillary endothelial cell growth and new blood vessel growth in animals
  • interrupting cell proliferation, inducing apoptosis
  • [155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha
  • resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha
  • prevents cytokine-induced vascular leakage and tumor metastasis
  • The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors
  • Nathan Goodyear on 01 Jun 18
     
    natural compounds to attach cancer explained.
Willow O'Donnell

Refurbished Alaris Gemini PC4 Infusion IV Pump - 0 views

www.polyvore.com/...thing

BuyIVpumps

shared by Willow O'Donnell on 11 Sep 14 - No Cached
  • Willow O'Donnell on 11 Sep 14
     
    Refurbished Alaris Gemini PC4 Infusion IV Pump The PC4 is a four channel infusion pump and controller that provides accurate and automatic infusions if drugs, fluids, whole blood and packed red blood cells.
Willow O'Donnell

We purchase your Refurbished Alaris Gemini PC2TX Infusion IV Pump - 0 views

www.shopstyle.com/...41112802

WepurchaseyourIVpumps Wepurchaseyourinfusionpumps

shared by Willow O'Donnell on 11 Sep 14 - No Cached
  • Willow O'Donnell on 11 Sep 14
     
    Refurbished Alaris Gemini PC2TX Infusion IV Pump The Refurbished Alaris Gemini PC2TX Infusion IV Pump is a two channel volumetric infusion pump and controller which provides accurate and automatic infusion of intravascular drugs, fluids, whole blood and packed red blood cells. The two channels are independent, and the PC-2TX may be operated as any combination of pump and/or controller.
Willow O'Donnell

http://willowmed.tumblr.com/post/103105457347/refurbished-alaris-gemini-pc2tx-infusion-... - 0 views

willowmed.tumblr.com/...-gemini-pc2tx-infusion-iv-pump

Buy IV pumps Purchase IV pumps

shared by Willow O'Donnell on 21 Nov 14 - No Cached
  • Willow O'Donnell on 21 Nov 14
     
    Refurbished Alaris Gemini PC2TX Infusion IV Pump The Refurbished Alaris Gemini PC2TX Infusion IV Pump is a two channel volumetric infusion pump and controller which provides accurate and automatic infusion of intravascular drugs, fluids, whole blood and packed red blood cells. The two channels are independent, and the PC-2TX may be operated as any combination of pump and/or controller.
Nathan Goodyear

Mechanisms of Edema Formation After Intracerebral Hemorrhage: Effects of Extravasated R... - 0 views

stroke.ahajournals.org/...2932

intracerebral hemorrhage brain edema

shared by Nathan Goodyear on 21 Mar 11 - No Cached
  • Nathan Goodyear on 21 Mar 11
     
    How the brain swells after intracerebral hemorrhage
Nathan Goodyear

Transfusion of Blood and Blood Products: Indications and Complications - - American Fam... - 0 views

www.aafp.org/...p719.html

Transfusion platelets anemia Thrombocytopenia "red blood cells" plasma cryoprecipitate

shared by Nathan Goodyear on 13 Nov 18 - No Cached
  • Nathan Goodyear on 13 Nov 18
     
    Good review of transfusion indications and complications
Nathan Goodyear

Inborn-like errors of metabolism are determinants of breast cancer risk, clinical respo... - 0 views

www.ncbi.nlm.nih.gov/...PMC6114970

cancer metabolism breast cancer glutamine glutamate aspartate oncogenes

shared by Nathan Goodyear on 24 Sep 18 - No Cached
  • We now recognize that human cancers evolve in an environment of metabolic stress. Rapidly proliferating tumor cells deprived of adequate oxygen, nutrients, hormones and growth factors up-regulate pathways that address these deficiencies to overcome hypoxia (HIF), vascular insufficiency (VEGF), growth factor deprivation (EGFR, HER2) and the loss of hormonal support (ER, PR, AR) all to enhance survival and proliferation
  • RAS, PI3K, TP53 and MYC
  • The results suggest that breast cancer could be preceded by systemic subclinical disturbances in glucose-insulin homeostasis characterized by mild, likely asymptomatic, IEM-like biochemical changes
  • ...16 more annotations...
  • The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis
  • The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8
  • four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders
  • growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy
  • glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population
  • blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure ​(Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure ​(Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively
  • glutamine consumption associated with parallel increases in glutamate and aspartate (Figure ​(Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”
  • Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death
  • changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy
  • lower Gln/Glu ratios inversely correlated with insulin resistance and the risk of diabetes
  • the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis
  • these metabolic disturbances would be expected to remain extant after therapeutic interventions
  • accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients
  • Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)
  • liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis
  • cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress
  • Nathan Goodyear on 24 Sep 18
     
    Breast cancer is a metabolic disease.  Now, where have I heard that cancer is a metabolic disease?
Nathan Goodyear

The distribution of ascorbic acid between various cellular components of blood, in norm... - 0 views

pubmed.ncbi.nlm.nih.gov/7082619

platelets vitamin C RBC plasma concentration monocytes red blood cells ascorbic acid

shared by Nathan Goodyear on 10 Jul 22 - No Cached
  • Nathan Goodyear on 10 Jul 22
     
    vitamin C has been documented to concentrate 80-fold (8,000%) above plasma levels.
Nathan Goodyear

Transdermal testosterone replacement therapy in men - 0 views

www.ncbi.nlm.nih.gov/...PMC3891651

Testosterone replacement transdermal low T male hormone hormones

shared by Nathan Goodyear on 05 Feb 14 - No Cached
  • a recent study has suggested that it may sometimes be inaccurate because of abnormal fluctuation of other circulating androgens
    • Nathan Goodyear
      Nathan Goodyear on 05 Feb 14
       
      The authors are referencing the increase in the suggestions to use other testing techniques i.e. saliva.
  • Testosterone therapy can inhibit hepcidin transcription and is associated with increased iron incorporation into red blood cells and increased erythropoietin concentrations
  • Transdermal TRT has a more favorable adverse effect profile when compared to buccal testosterone formulations
  • ...13 more annotations...
  • Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1)
  • the recommendation for injectable testosterone esters is to check the serum concentration midway between injections
  • it is recommended for serum testosterone to be evaluated 3 to 12 hours after application of the transdermal patch
  • testosterone concentrations should be checked 2–3 months after initiation of therapy and after adjusting the dose
  • a study from 1989 utilizing testosterone transdermally containing 5, 10, or 15 mg of testosterone showed that peak concentrations of testosterone were achieved 3 to 8 hours after scrotal application in hypogonadal men
  • It is used for many medications and has the advantage of high bioavailability, absence of hepatic first pass metabolism, increased therapeutic efficacy, and steadiness of plasma concentrations of the drug
  • evaluate serum testosterone at the end of the dosing interval for testosterone pellets
  • increased amount of fat leads to increased extragonadal aromatase activity, resulting in increased concentrations of estradiol. High circulating concentrations of estradiol down regulate the HPG axis and decrease the amount of circulating testosterone
  • Up to 80% of plasma estradiol originates from aromatization of testosterone and less than 20% of estradiol in the circulation is secreted by the testes
  • A PSA concentration, digital rectal examination, and hematocrit should be performed at baseline and at 3 months, 6 months, then yearly after TRT is initiated.
  • measure serum testosterone any time after the patient has been on treatment with gel for at least 1 week
  • If the hematocrit rises above 54%, treatment should be discontinued
  • elderly men having higher estradiol serum concentrations than postmenopausal women
Nathan Goodyear

Prognostic value of RDW in cancers: a systematic review and meta-analysis - 0 views

www.ncbi.nlm.nih.gov/...PMC5362543

RDW red blood cell distribution width cancer

shared by Nathan Goodyear on 28 Jun 19 - No Cached
  • Nathan Goodyear on 28 Jun 19
     
    Elevated RDW associated with poor outcomes and poor prognosis in patients with cancer.
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