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Nathan Goodyear

The Contribution of Cytotoxic Chemotherapy to 5-year Survival in Adult Malignancies | C... - 0 views

www.scribd.com/...Survival-in-Adult-Malignancies

chemotherapy cancer

shared by Nathan Goodyear on 15 May 18 - No Cached
  • In this group, the 5-year survivalrateduesolelytocytotoxicchemotherapywas14%
  • There is also no convincing evidence that usingregimens with newer and more expensive drugs are anymore beneficial than the regimens used in the 1970s
  • two systematic reviews of chemotherapy inrecurrent or metastatic breast cancer have not been able toshow any survival benefit
  • ...12 more annotations...
  • The five most common adult malignancies (colorectal, breast, prostate, melanoma and lung cancer)
  • n breast cancer, the optimal regimen(s) for cytotoxicchemotherapy in recurrent/metastatic disease are still notdefined, despite over 30 years of ‘research’ and a plethora of RCTs since the original Cooper regimen was published in1969
  • The five most ‘chemo-sensitive’ cancers,namely testis, Hodgkin’s disease and non-Hodgkin’s lym- phoma, cervix and ovary
  • only 13 out of the 22 malignancies evaluated showed any improvement in 5-year survival, and theimprovement was greater than 10% in only three of those13 malignancies
  • the contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults is 2.3% in Australia and 2.1% in the USA
  • a benefit of less than 2.5% is likely to be applicable in other developed countries
  •   Overview The Contribution o
  • the benefit of cytotoxic chemotherapy may have been overestimated for cancers of oesophagus, stomach,rectum and brain.
  • this reflects the presentation of results as a ‘reduction in risk’ rather than asan absolute survival benefit[89,90]and by exaggerating theresponse rates by including ‘stable disease’
  • recent studies have documented impaired cognitive function inwomen receiving adjuvant treatment for breast cancer
  • the 5-year survival rate due solely to cytotoxicchemotherapy was 1.6%
  • the value of palliative chemotherapy has beenquestioned
  • Nathan Goodyear on 15 May 18
     
    Incredibly low impact of cytotoxic chemotherapy despite its wide spread utilization.  This article referenced cost yet did not evaluate the cost of cytotoxic side effect.  The question to answer: is Cytotoxic chemotherapy a valid treatment, at all, for the majority of cancers.
Nathan Goodyear

Toxicity of the spike protein of COVID-19 is a redox shift phenomenon: A novel therapeu... - 0 views

www.sciencedirect.com/...S0891584923005014

COVID19 COVID-19 cancer inflammation SARS-CoV-2 spike proteins COVID spikeopathy

shared by Nathan Goodyear on 01 Sep 23 - No Cached
  • Redox shift is due to Warburg effect and mitochondrial impairment.
  • Redox shift is due to Warburg effect and mitochondrial impairment.
  • Redox shift is due to Warburg effect and mitochondrial impairment.
  • ...88 more annotations...
  • The cytokine storm is a consequence of mitochondrial dysfunction
  • The cytokine storm is a consequence of mitochondrial dysfunction
  • The cytokine storm is a consequence of mitochondrial dysfunction
  • The cytokine storm is a consequence of mitochondrial dysfunction
  • Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity
  • Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity
  • Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity
  • Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity
  • most diseases display a form of anabolism due to mitochondrial impairment
  • most diseases display a form of anabolism due to mitochondrial impairment
  • most diseases display a form of anabolism due to mitochondrial impairment
  • infection by Covid-19 follows a similar pattern
  • chronic inflammation
  • Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction
  • Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction
  • Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction
  • Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction
  • infection by Covid-19 follows a similar pattern
  • unrelenting anabolism leads to the cytokine storm,
  • unrelenting anabolism leads to the cytokine storm,
  • unrelenting anabolism leads to the cytokine storm,
  • chronic inflammation
  • chronic inflammation
  • infection by Covid-19 follows a similar pattern
  • Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism
  • Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism
  • Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism
  • Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism
  • Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism
  • Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism
  • direct consequence of redox iMeBalance, itself a consequence of decreased energy yield by the mitochondria
  • direct consequence of redox iMeBalance, itself a consequence of decreased energy yield by the mitochondria
  • mitochondrial dysfunction and increased levels of lactate, which are important characteristics of metabolic shift and Warburg effect in many diseases
  • mitochondrial dysfunction and increased levels of lactate, which are important characteristics of metabolic shift and Warburg effect in many diseases
  • increased lactate dehydrogenase activity (LDH) was observed in COVID-19 patients
  • increased lactate dehydrogenase activity (LDH) was observed in COVID-19 patients
  • almost every disease presents an increased anabolism
  • almost every disease presents an increased anabolism
  • cell division is the most sophisticated way to release entropy
  • cell division is the most sophisticated way to release entropy
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Wow
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Wow
  • transition from catabolism to anabolism is driven by a redox shift
  • transition from catabolism to anabolism is driven by a redox shift
  • viral spike protein binds to ACE2 receptor of the host cell [22,23].
  • redox signaling plays an important role in regulating immune function and inflammation, and disruptions in this signaling can lead to excessive cytokine production and immune system activation
  • Aging is associated with a poor control of the redox balance
  • thiol/disulfide homeostasis
  • reduced extracellular environment in the elderly and the increased susceptibility to Covid-19 infection
  • reduced extracellular environment in the elderly and the increased susceptibility to Covid-19 infection
  • Redox signaling tightly modulates the inflammatory response and oxidative stress has been reported in acute Covid-19
  • People at high risk are the elderly, patients suffering from metabolic syndrome such as obesity, or those suffering from chronic diseases such as cancer or inflammation
  • COVID-19 patients with severe disease have higher levels of oxidative stress markers and lower antioxidant levels
  • oxidative stress can activate the NLRP3 inflammasome, which is a protein complex that plays a key role in the cytokine storm
  • inflammation leads to the formation of ROS and RNS, while redox iMeBalance results in cellular damage, which in turn triggers an inflammatory response
  • persistently elevated mtROS triggers endothelial dysfunction and inflammation, which results in a vicious loop involving ROS, inflammation, and mitochondrial dysfunction
  • Damaged mitochondria releasing ROS induce inflammation via the NLRP3 inflammasome
  • Damaged mitochondria releasing ROS induce inflammation via the NLRP3 inflammasome
  • reduced environment during the cytokine storm
  • IL-2 is highly up-regulated in Covid-19 patients [37], and IL-2 is known to significantly stimulate the generation of NO in patients
  • Nitric acid is also the key mediator of IL-2-induced hypotension and vascular leak syndrome
  • mitochondrial dysfunction has been linked to the pathogenesis of Covid-19
  • mitochondrial dysfunction triggered by SARS-CoV-2 leads to damage to the mitochondria
  • mitochondrial dysfunction triggered by SARS-CoV-2 leads to damage to the mitochondria
  • As catabolism is decreased, entropy is released through anabolism
  • Elevated levels of lactate, a characteristic of the Warburg effect, were also reported in the high-risk Covid-19
  • elevated levels of ventricular lactic acid consistent with oxidative stress
  • A decrease of ΔΨm is implicated in several inflammation-related diseases
  • decrease in ΔΨm in leucocytes from Covid-19 patients
  • vaccinated with RNA or DNA vaccines triggering the synthesis of the viral spike protein in human cells
  • viral reactivation in varicella-zoster virus [55] or hepatitis [56], coagulopathy and resulting stroke and myocarditis following both DNA-based vaccines [57] and RNA-based vaccines
  • Covid-19, mitochondrial impairment
  • characteristic of the Warburg effect is present in almost every disease and appears to be a central feature in most of the hallmarks of cancer
  • inflammation, mitochondrial dysfunction and increased lactate concentrations in the extracellular fluid
  • In Covid-19, like any inflammation, there is a metabolic rewiring where cells rely on glycolysis
  • As the mitochondria are impaired, the infected cell cannot catabolize efficiently. It will release lactic acid in the blood stream
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Mitochondrial impairment
  • Striking similarities are seen between cancer, Alzheimer's disease and Covid-19, all related to the Warburg effect
  • Cancer, inflammation, Alzheimer's, and Parkinson's diseases share a common peculiarity, the inability of the cell to export entropy outside the body in the harmless form of heat
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Entropy: lack of order or predictability; gradual decline into disorder.
  • MEB relieves the Warburg effect [87], improves memory [77], is active in the treatment of depressive episodes [79,80] and reduces the importance of ischemic strokes
  • MEB relieves the Warburg effect [87], improves memory [77], is active in the treatment of depressive episodes [79,80] and reduces the importance of ischemic strokes
  • MEB has been shown to inhibit SARS-Cov-2 replication in vitro
  • MEB has been shown to inhibit SARS-Cov-2 replication in vitro
  • It has been shown that Covid-19-patients treated with MEB, have a significant reduction in hospital stay duration and mortality
  • MeB is an acceptor-donor molecule
  • MeB + can take a pair of electrons (of H atoms) and MeBH can release this pair easily, so that MeB is partially recycled like a catalyst
  • MeB acts as an electron bridge between a donor (FADH2, FMNH, NADH) and an acceptor (complex IV of ETC or oxygen itself)
  • As a coenzyme of pyruvate dehydrogenase (PDH), alpha-lipoic acid (ALA) initiates the formation of acetyl-CoA to feed the TCA cycle
  • ALA enhances the catabolism of carbon. cycle and therefore may reduce the Warburg effect and consequently, lactate production
  • Methylene Blue plays a similar role after the TCA cycle, by carrying electrons to complex IV of the electron transport chain
  • Drugs such as lipoic acid and MeB, which target the metabolism, decrease the redox shift by increasing catabolism
Nathan Goodyear

Anticancer mechanisms of cannabinoids - 0 views

www.ncbi.nlm.nih.gov/...PMC4791144

THC cannabinoids cancer

shared by Nathan Goodyear on 18 Sep 18 - No Cached
  • modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival
  • cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals
  • Cannabis sativa L. (marijuana)
  • ...41 more annotations...
  • of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations
  • Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors
  • the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins
  • transient receptor potential cation channel subfamily V, member 1
  • orphan G protein–coupled receptor 55
  • Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation
  • two major cannabinoid-specific receptors—cb1 and cb2
  • cardiovascular tone, energy metabolism, immunity, and reproduction
  • cannabinoids are well known to exert palliative effects in cancer patients
  • best-established use is the inhibition of chemotherapy-induced nausea and vomiting
  • thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer
  • cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue
  • cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer
  • pharmacologic activation of cannabinoid receptors decreases tumour growth
  • endocannabinoid signalling can also have a tumour-suppressive role
  • pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids
  • most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation
  • impair tumour angiogenesis and block invasion and metastasis
  • thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation
  • Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death
  • autophagy is important for cannabinoid antineoplastic activity
  • autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death
  • the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors
  • glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy
  • other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions
  • thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations
  • cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors
  • In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi
  • In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis
  • cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture
  • the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2
  • cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis
  • cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts
  • ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer
  • recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth
  • combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells
  • Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively
  • Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity
  • Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth
  • Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models
  • pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids
  • Nathan Goodyear on 18 Sep 18
     
    Good review of the anticancer effects of cananbinoids.
Nathan Goodyear

JCI - Inflammatory links between obesity and metabolic disease - 0 views

www.jci.org/57132

obesity overweight weight-loss inflammation metabolic disease

shared by Nathan Goodyear on 04 Jan 12 - No Cached
  • metainflammation
  • The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time
  • It is clear that inflammation participates in the link between obesity and disease
  • ...25 more annotations...
  • Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines (10), decreases in protective factors (e.g., adiponectin; ref. 11), and communication between inflammatory and metabolic cells
  • adipose tissue macrophage (ATM)
  • Physiologic enhancement of the M2 pathways (e.g., eosinophil recruitment in parasitic infection) also appears to be capable of reducing metainflammation and improving insulin sensitivity (27).
  • increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate (21–23).
  • The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ
  • well-known regulators of lipid metabolism and mitochondrial activity
  • Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65).
  • inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34)
  • Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass
  • JNK, TLR4, ER stress)
  • NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells
  • Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state (M1) that generates bactericidal or Th1 responses typically associated with obesity
  • DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59)
  • saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60)
  • Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57)
  • Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73)
  • Placental inflammation is a characteristic of maternal obesity
  • a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74
  • Of these PRRs, TLR4 has received the most attention, as this receptor can be activated by free FAs to generate proinflammatory signals and activate NF-κB
  • Nod-like receptor (NLR) family of PRRs
  • ceramides and sphingolipids
  • The adipokine adiponectin has long been recognized to have positive benefits on multiple cell types to promote insulin sensitivity and deactivate proinflammatory pathways.
  • adiponectin stimulates ceramidase activity and modulates the balance between ceramides and sphingosine-1-phosphate
  • Inhibition of ceramide production blocks the ability of saturated FAs to induce insulin resistance (101)
  • NF-κB, obesity also activates JNK in insulin-responsive tissues
  • Nathan Goodyear on 04 Jan 12
     
    must read to see our current knowledge on the link between inflammation and obesity.
Nathan Goodyear

Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views

nutritionandmetabolism.biomedcentral.com/...s12986-017-0178-2

ketogenic diet ketogenic press-pulse hyperbaric oxygen therapy HBOTnutrition diet cancer HBOT IVC IV vitamin C DCA dichloracetic acid cancer therapy cancer treatment alternative cancer treatment

shared by Nathan Goodyear on 09 Jul 17 - No Cached
mamdouh_hfz liked it
  • A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
  • “pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
  • Neoplasia involving dysregulated cell growth is the biological endpoint of the disease
  • ...84 more annotations...
  • Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
  • cancer is predicted to overtake heart disease as the leading cause of death in Western societies
  • cancer can also be recognized as a metabolic disease.
  • glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
  • Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
  • persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
  • Otto Warburg first proposed that all cancers arise from damage to cellular respiration
  • The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
  • the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
  • The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
  • Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
  • Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
  • all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
  • The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
  • respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
  • data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
  • Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
  • In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival
  • Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
  • Glucose and glutamine act synergistically for driving rapid tumor cell growth
  • Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions
  • Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
  • Hif-1α stabilization enhances aerobic fermentation
  • targeting glucose and glutamine will deprive the microenvironment of fermentable fuels
  • Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
  • Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
  • Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
  • Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
  • Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
  • It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
  • Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
  • The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
  • According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
  • A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
  • Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
  • Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
  • The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
  • Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      reason to eliminate glutamine in cancer patients and even GSH with cancer patients
  • It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
  • Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
  • glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
  • In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
  • Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
  • Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
  • Ketone bodies and fats are non-fermentable fuels
  • Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
  • Apoptosis under energy stress is greater in tumor cells than in normal cells
  • A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
  • . This energy stress acts as a press disturbance
  • Drugs that target availability of glucose and glutamine would act as pulse disturbances
  • Hyperbaric oxygen therapy can also be considered another pulse disturbance
  • The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
  • Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
  • Protein amino acids can be metabolized to glucose through the Cori cycle
  • The fats in KDs used clinically also contain more medium chain triglycerides
  • Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
  • Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
  • GKI values of 1.0 or below are considered therapeutic
  • The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
  • It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
  • The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
  • Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
  • Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      Ketones are much more than energy adaptabilit, but actually are therapeutic.
  • ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
  • Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
  • Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
  • In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
  • Ketone supplementation has also been shown to reduce anxiety behavior in animal models
  • This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
  • lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
  • Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      oxaloacetate is a glycolytic inhibitor, as is doxycycline, and IVC.
  • A synergistic interaction of the KD diet plus radiation was seen
  • It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
  • Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
  • HBOT also increases oxidative stress and membrane lipid peroxidation of GBM cells in vitro
  • The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
  • Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
  • Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
  • Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
  • GBM and use glutamine as a major fuel
  • Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
  • Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
  • Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
  • Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
  • Nathan Goodyear on 09 Jul 17
     
    Cancer is a mitochondrial disease? So says the well published Dr Seyfried. Glucose and glutamine drive cancer growth.
Nathan Goodyear

Histamine dihydrochloride and low-dose interleukin-2 as post-consolidation im... - 0 views

www.academia.edu/...rapy_in_acute_myeloid_leukemia

AML leukemia acute myeloid leukemia IL-2 histamine cancer NK cells

shared by Nathan Goodyear on 31 May 18 - No Cached
  • IL-2 is a central T cell-derived cytokine, which induces NK cell and T cell proliferation, differentiation and activation, and also stim-ulates the production of secondary immunostimulatory cytokines
  • combination of histamine and IL-2 thus triggers efficient NK cell-mediated killing of several types of leukemic cells, including freshly recovered human AML blasts
  • histamine improves the effects of IL-2 on T cell activation
  • ...3 more annotations...
  • principal action of histamine is to protect cytotoxic lymphocytes from myeloid-cell-induced inactivation, thus improving the efficiency of the T and NK cell stimulation achieved by IL-2
  • random-ized Phase II study of patients with renal cell carcinoma further support the suggestion that the combination of HDC and IL-2 improves lymphocyte functions
  • HDC improves the effectiveness of IL-2-induced T and NK cell activation in cancer patients, as predicted in preclinical models
  • Nathan Goodyear on 31 May 18
     
    histamine dihydrochloride enhances immune effects of NK cells in IL02 therapy; specifically in this analysis in AML, the histamin prevented inactivation of the IL-2 activated NK cells.
Nathan Goodyear

Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic... - 0 views

www.ebiomedicine.com/...fulltext

multiple myeloma vitamin C IV vitamin C smoldering myeloma cancer

shared by Nathan Goodyear on 25 Sep 17 - No Cached
  • Recent reports indicate that a certain ROS concentration is required for high-dose vitamin C to induce cytotoxicity in cancer cells.
  • The generation of ascorbyl- and H2O2 radicals by PAA increases ROS stress in cancer cells
  • In this study, we report that PAA is efficacious in killing MM cells in vitro and in vivo models, which generated levels of 20–40 mM ascorbate and 500 nM ascorbyl radicals after intraperitoneal administration of 4 g ascorbate per kilogram of body weight (Chen et al., 2008Chen et al., 2008), in xenograft MM mice
  • ...33 more annotations...
  • These data suggest that PAA may show a therapeutic advantage to blood cancers vs solid tumors because of the communication between tumor cells and blood plasma
  • These results strongly suggest that the mechanism of PAA killing of MM cells is indeed iron-dependent
  • These results suggest that PAA administration in SMM may be able to prevent progression to symtomatic MM
  • A recent study by Yun and colleagues demonstrated that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, but spares normal cells
  • RAS family genes show the most frequent mutations in MM. KRAS, NRAS and BRAF are mutated in 22%, 20% and 7% of MM samples
  • the disease stage rather than the mutation of RAS and/or BRAF is the major predictive factor for PAA sensitivity in MM treatment
  • Other molecular mechanisms including ATP depletion and ATM-AMPK signaling have been reported to explain PAA-induced cell death
  • our pilot study also suggested that PAA could overcome drug resistance to bortezomib in MM cells
  • Our findings complement reported studies and further address the mechanism of action using clinical samples in which we observed that PAA killed tumor cells with high iron content, suggesting that iron might be the initiator of PAA cytotoxicity
  • combination of PAA with standard therapeutic drugs, such as melphalan, may significantly reduce the dose of melphalan needed
  • Combined treatment of reduced dose melphalan with PAA achieved a significantly longer progression-free survival than the same dose of melphalan alone.
  • These data also suggest that the bone marrow suppression induced by high-dose melphalan can be ameliorated by the combination of PAA with lower dose of melphalan because of the lack of toxicity of PAA on normal cells with low iron content.
  • if creatinine clearance is <30 mL/min, high dose ascorbic acid should be not administrated.
  • In MM preclinical and clinical studies, ascorbate was used as an adjunct drug and showed controversial results (Harvey et al., 2009, Perrone et al., 2009, Held et al., 2013, Sharma et al., 2012, Nakano et al., 2011, Takahashi, 2010, Sharma et al., 2009, Qazilbash et al., 2008). However, none of these tests used pharmacological doses of ascorbate and intravenous administration
  • Multiple myeloma (MM) is a plasma cell neoplasm.
  • Cameron and Pauling reported that high doses of vitamin C increased survival of patients with cancer
  • pharmacologically dosed ascorbic acid (PAA) 50–100 g (Chen et al., 2008, Padayatty et al., 2004, Hoffer et al., 2008, Padayatty et al., 2006, Welsh et al., 2013), administered intravenously, has potent anti-cancer activity and its role as anti-cancer therapy is being studied at the University of Iowa and in other centers
  • In the presence of catalytic metal ions like iron, PAA administered intravenously exerts pro-oxidant effects leading to the formation of highly reactive oxygen species (ROS), resulting in cell death
  • the labile iron pool (LIP) is significantly elevated in MM cells
  • The survival of CD138+ cells in vitro was significantly decreased following PAA treatment in all 9 MM
  • In contrast, no significant change of cell viability was observed in CD138− BM cells from the same patients
  • The same effect of PAA was also observed in the SMM patients
  • no response to PAA was detected in CD138+ cells from the 2 MGUS patients
  • the combination of melphalan plus PAA showed greater tumor burden reduction than each drug alone, suggesting a synergistic activity between these two drugs
  • Both catalase and NAC protect cells from oxidative damage
  • cells pretreated with NAC and catalase became resistant to PAA even at high doses
  • adding deferoxamine (DFO), an iron chelator, to OCI-MY5 cells before PAA treatment was also sufficient to prevent PAA-induced cellular death
  • iron is essential for PAA to achieve its anti-cancer activity
  • PAA induced early necrosis (Fig. 3Fig. 3A, 60 min) followed by late apoptosis
  • results further indicated that PAA induced mitochondria-mediated apoptosis
  • PAA by reacting with LIP and generating ROS induces mitochondria-mediated apoptosis in which AIF1 cleavage is important for cell death.
  • ROS and H2O2 are well known factors mediating PAA-induced cancer cell death
  • PAA was sensitive to all 9 MMs and 2 SMMs
  • Nathan Goodyear on 25 Sep 17
     
    animal study finds high-dose, pharmacologic vitamin C found to kill multiple myeloma cells via pro-oxidant effect found in similar studies in dealing with different cancers.
Nathan Goodyear

Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androg... - 0 views

www.nature.com/...srep01528.html

prostate cancer 3-alpha androstanediol 3-beta androstanediol DHT metabolite metabolites

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • PSA levels in media were increased by 3α-diol
  • Similarly to 3α-diol, 3β-diol also increased PSA levels in media in a concentration-dependent manner
  • intracellular DHT is synthesized from inactive androgen 3α- and 3β-diol via different pathways in prostate cancer cells
  • ...12 more annotations...
    • Nathan Goodyear
      Nathan Goodyear on 15 Jul 15
       
      error in statement: DHT metabolites are not inactive, they just don't activate AR.
  • 3β-diol can be a precursor of DHT in prostate cancer cells.
  • serum 3α-diol G levels reflect the androgen milieu in localized prostate cancer patients receiving ADT
  • A few studies reported that 3β-diol is a potential ligand of estrogen receptor β (ERβ) and has an antiproliferative effect
  • our results revealed that 3β-diol is potentially a precursor of DHT in prostate cancer cells
  • Bauman et al. showed that 3α-diol is inactive at AR, but induces prostate growth
  • Prostate cancer cells promoted synthesis from the DHT metabolite 3α-diol during the long duration of ADT
    • Nathan Goodyear
      Nathan Goodyear on 15 Jul 15
       
      the authors highlight the suggestion is that 3alpha-diol's activity is via 3alpha-HSD, but fail to mention that it is known that 3alpha-diol interacts with the ER-alpha in the prostate.
  • verified the synthesis of DHT from 3α- or 3β-diol via different pathways in prostate cancer cells in this study
  • HSD17B6 expression levels in prostate cancer can be useful for the diagnosis of high-risk prostate cancer
  • serum 3α-diol G levels reflect the adrenal androgen milieu in localized prostate cancer patients
  • 3α- and 3β-diol has a much more significant role in intratumoral androgen metabolism during ADT
  • Nathan Goodyear on 27 Jan 14
     
    DHT metabolites play an important role of intra-prostate DHT synthesis in those following ADT.  This is a proposed mechanism for the failure rate and aggressive nature of prostate cancer that fails ADT.   3-alpha androstanediol is converted via 3 alpha HSD back to DHT.  In contrast, 3-beta androstanediol cannot.
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

Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind... - 0 views

press.endocrine.org/...jc.2011-1329

T4 T3 hypothyroid hypothyroidism thyroid lipids weight loss metabolism cholesterol hormones

shared by Nathan Goodyear on 24 Sep 14 - No Cached
  • tissue euthyroidism is the net result of multiple steps including conversion of the prohormone T4 into its active metabolite T3, which is ultimately responsible for signaling at the end-organ target level
  • The circulating and intracellular pools of T3 of treated hypothyroid patients (i.e. devoid of endogenous TH production) depend entirely on the conversion of exogenous l-T4 into T3
  • TH is the major regulator of basal metabolic rate
  • ...8 more annotations...
  • The substitution of l-T3 for l-T4 caused a significant weight loss
  • The substitution of l-T3 for l-T4 caused a significant reduction in lipid parameters
  • Despite the increase in serum T3, the l-T3 treatment did not cause major changes in cardiovascular or musculoskeletal function, as indicated by the echocardiographic and maximal exercise tolerance tests and DXA studies.
  • The changes in serum lipid metabolism parameters are similar to the effects observed with drugs approved for the treatment of dyslipidemia
  • This differential response appears to be limited to the lipid metabolism and SHBG, whereas no differences in indices of insulin resistance were detected. This is remarkable because hyperthyroid states are associated with an increase in hepatic gluconeogenesis (37), and overt thyrotoxicosis is a known cause of secondary diabetes.
  • TH action is increased in the liver, and the SHBG increase supports this hypothesis
  • Similarly, no significant differences were observed in blood pressure, heart rate, or endothelial vascular function
  • In conclusion, the results of this pharmacology, proof-of-concept study indicate that replacement therapy of hypothyroidism with l-T3, compared with l-T4 causes weight loss and favorable changes in the lipid profile without appreciable side effects
  • Nathan Goodyear on 24 Sep 14
     
    Crossover study finds T3 versus T4 results in more weight loss, improved lipid management and increased SHBG without any adverse cardiovascular effects.   The T3 was dosed 3 x daily due to its short half life compared to T4.
Nathan Goodyear

Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Post-Tr... - 0 views

ajp.amjpathol.org/...fulltext

Lyme Lyme disease borrelia burgdorferi

shared by Nathan Goodyear on 14 Dec 17 - No Cached
  • In this study, we have demonstrated microscopic pathology ranging from minimal to moderate in multiple different tissues previously reported to be involved with LD, including the nervous system (central and peripheral), heart, skeletal muscle, joint-associated tissues, and urinary bladder 12 to 13 months following tick-inoculation of rhesus macaques by Bb strain B31
  • Based on histomorphology, inflammation consisted predominantly of lymphocytes and plasma cells, with rare scattered histiocytes
  • in rare instances, morphologically intact spirochetes were observed in inflamed brain and heart tissue sections from doxycycline-treated animals
  • ...41 more annotations...
  • colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable
  • The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment
  • The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD
  • In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal
  • Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum
  • We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro
  • The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic
  • The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well
  • Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).
  • we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.
  • Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.
  • In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment
  • This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.
  • The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s
  • Lyme, Connecticut.
  • Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere
  • approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6
  • Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)
  • ‘post-treatment Lyme disease syndrome’ (PTLDS)
  • host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic
  • inflammatory responses to residual antigens from dead organisms
  • residual tissue damage following pathogen clearance;
  • autoimmune responses, possibly elicited by antigenic mimicry
  • Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses
  • Ten male rhesus macaques
  • half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.
  • Minimal and focal lymphoplasmacytic inflammation
  • inflammation was observed in the leptomeninges overlying a section of temporal cerebral cortex
  • Minimal localized lymphoplasmacytic choroiditis
  • Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces
  • Inflammation was observed in 56% (5/9) of the NHPs irrespective of treatment group
  • For all animals, inflammation was reserved to perineural tissue
  • The treatment lasted 28 days
  • Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs
  • A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal
  • mild, multifocal lymphoplasmacytic inflammation was observed in one doxycycline-treated animal
  • three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures
  • 10% to -20% of human patients treated
  • Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)
  • and the rapid clearance of dead spirochetes in a murine model
  • higher doses may be needed to combat neuroborreliosis
  • Nathan Goodyear on 14 Dec 17
     
    persistent borrelia burgdorferia were found in the brain (2) and the heart (1) up to 13 months post standard antibiotic treatment suggesting borrelia burdorferia, the cause of Lyme, can persist in a chronic, persistant state poste acute treatment.
Nathan Goodyear

Plasma lipoproteins: composition, structure and biochemistry - 0 views

lipidlibrary.aocs.org/...index.htm

apolipoproteins cholesterol VLDL chylomicrons LDL HDL lipoproteins biochemistry

shared by Nathan Goodyear on 21 May 13 - No Cached
  • triacylglycerols
  • The most abundant lipid constituents are triacylglycerols, free cholesterol, cholesterol esters and phospholipids (phosphatidylcholine and sphingomyelin especially ), though fat-soluble vitamins and anti-oxidants are also transported in this way
  • the lipoprotein aggregates should be described in terms of the different protein components or apoproteins (or 'apolipoproteins'
  • ...8 more annotations...
  • Density is determined largely by the relative concentrations of triacylglycerols and proteins and by the diameters of the broadly spherical particles
  • these classes can be further refined by improved separation procedures, and intermediate-density lipoproteins (IDL) and subdivisions of the HDL (e.g. HDL1, HDL2, HDL3 and so forth
  • the main groups are classified as chylomicrons (CM), very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), based on the relative densities of the aggregates on ultracentrifugation
  • the various lipid components should not be considered as absolute, as they are in a state of constant flux
  • Apo A1 is the main protein component of HDL
  • Apo A2 is the second most important HDL apolipoprotein
  • Lipoproteins are spherical (VLDL, LDL, HDL) to discoidal (nascent HDL) in shape with a core of non-polar lipids, triacylglycerols and cholesterol esters, and a surface monolayer, ~20Å thick, consisting of apoproteins, phospholipids and non-esterified cholesterol, which serves to present a hydrophobic face to the aqueous phase
  • The lipoproteins can be categorised simplistically according to their two main metabolic functions. The principal role of the chylomicrons and VLDL is to transport triacylglycerols ‘forward’ as a source of fatty acids from the intestines or liver to the peripheral tissues. In contrast, the HDL remove excess cholesterol from peripheral tissues and deliver it to the liver for excretion in bile in the form of bile acids (‘reverse cholesterol transport’). While these functions are considered separately here for convenience, it should be recognised that the processes are highly complex and inter-related, and they involve transfer of apoproteins, enzymes and lipid constituents among the heterogeneous mix of all the lipoprotein fractions.
  • Nathan Goodyear on 21 May 13
     
    Awesome review of apolipoproteins, their function, and their metabolism.
Nathan Goodyear

The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pa... - 0 views

www.ncbi.nlm.nih.gov/...PMC4287931

ivermectin cancer WTF Selamectin

shared by Nathan Goodyear on 19 Mar 18 - No Cached
  • WNT signaling
  • early colon cancers commonly display loss of function of the tumor suppressor Adenomatous polyposis coli (APC), a key component of the β-CATENIN destruction complex
  • Other cancers also show an active canonical WNT pathway; these include carcinomas of the lung, stomach, cervix, endometrium, and lung as well as melanomas and gliomas
  • ...31 more annotations...
  • In normal embryogenesis and homeostasis, the canonical WNT pathway is activated by secreted WNT ligands produced in highly controlled context-dependent manners and in precise amounts. WNT activity is transduced in the cytoplasm, inactivates the APC destruction complex, and results in the translocation of activate β-CATENIN to the nucleus, where it cooperates with DNA-binding TCF/LEF factors to regulate WNT-TCF targets and the ensuing genomic response
  • beyond the loss of activity of the APC destruction complex, for instance throughAPC mutation, phosphorylation of β-CATENIN at C-terminal sites is required for the full activation of WNT-TCF signaling and the ensuing WNT-TCF responses in cancer.
  • The WNT-TCF response blockade that we describe for low doses of Ivermectin suggests an action independent to the deregulation of chloride channels
  • involve the repression of the levels of C-terminally phosphorylated β-CATENIN forms and of CYCLIN D1, a critical target that is an oncogene and positive cell cycle regulator.
  • the Avermectin single-molecule derivative Selamectin, a drug widely used in veterinarian medicine (Nolan & Lok, 2012), is ten times more potent acting in the nanomolar range
  • Ivermectin also diminished the protein levels of CYCLIN D1, a direct TCF target and oncogene, in both HT29 and H358 tumor cells
  • Activated Caspase3 was used as a marker of apoptosis by immunohistochemistry 48 h after drug treatment. Selamectin and Ivermectin induced up to a sevenfold increase in the number of activated Caspase3+ cells in two primary (CC14 and CC36) and two cell line (DLD1 and Ls174T) colon cancer cell types (Fig​(Fig2C).2C). All changes were significative
  • The strong downregulation of the expression of the intestinal stem cell genesASCL2 andLGR5 (van der Flieret al, 2009; Scheperset al, 2012; Zhuet al, 2012b) by Ivermectin and Selamectin (Fig​(Fig2D)2D) raised the possibility that these drugs could affect WNT-TCF-dependent colon cancer stem cell behavior
  • Pre-established H358 tumors responded to Ivermectin showing a ˜ 50% repression of growth
  • Ivermectin hasin vivo efficacy against human colon cancer xenografts sensitive to TCF inhibition with no discernable side effects
  • Ivermectin (Campbellet al, 1983), an off-patent drug approved for human use, and related macrocyclic lactones, have WNT-TCF pathway response blocking and anti-cancer activities
  • these drugs block WNT-TCF pathway responses, likely acting at the level of β-CATENIN/TCF function, affecting β-CATENIN phosphorylation status.
  • anti-WNT-TCF activities of Ivermectin and Selamectin
  • Ivermectin has a well-known anti-parasitic activity mediated via the deregulation of chloride channels, leading to paralysis and death (Hibbs & Gouaux, 2011; Lynagh & Lynch, 2012). The same mode of action has been suggested to underlie the toxicity of Ivermectin for liquid tumor cells and the potentiation or sensitization effect of Avermectin B1 on classical chemotherapeutics
  • the specificity of the blockade of WNT-TCF responses we document, at low micromolar doses for Ivermectin and low nanomolar doses for Selamectin, indicate that the blockade of WNT-TCF responses and chloride channel deregulation are distinct modes of action
  • What is key then is to find a dose and a context where the use of Ivermectin has beneficial effects in patients, paralleling our results with xenografts in mice.
  • Cell toxicity appears at doses greater (> 10 μM for 12 h or longer or > 5 μM for 48 h or longer for Ivermectin) than those required to block TCF responses and induce apoptosis.
  • Our data point to a repression of WNT-β-CATENIN/TCF transcriptional responses by Ivermectin, Selamectin and related macrocylic lactones.
  • (i) The ability of Avermectin B1 to inhibit the activation of WNT-TCF reporter activity by N-terminal mutant (APC-insensitive) β-CATENIN as detected in our screen
  • (ii) The ability of Avermectin B1, Ivermectin, Doramectin, Moxidectin and Selamectin to parallel the modulation of WNT-TCF targets by dnTCF
  • (iii) The finding that the specific WNT-TCF response blockade by low doses of Ivermectin and Selamectin is reversed by constitutively active TCF
  • (iv) The repression of key C-terminal phospho-isoforms of β-CATENIN resulting in the repression of the TCF target and positive cell cycle regulator CYCLIN D1 by Ivermectin and Selamectin
  • (v) The specific inhibition ofin-vivo-TCF-dependent, but notin-vivo-TCF-independent cancer cells by Ivermectin in xenografts.
  • These results together with the reduction of the expression of the colon cancer stem cell markersASCL2 andLGR5 (e.g., Hirschet al, 2013; Ziskinet al, 2013) raise the possibility of an inhibitory effect of Ivermectin, Selamectin and related macrocyclic lactones on TCF-dependent cancer stem cells.
  • the capacity of cancer cells to form 3D spheroids in culture, as well as the growth of these, is also WNT-TCF-dependent (Kanwaret al, 2010) and they were also affected by Ivermectin treatment
  • If Ivermectin is specific, it should only block TCF-dependent tumor growth. Indeed, the sensitivity and insensitivity of DLD1 and CC14 xenografts to Ivermectin treatment, respectively, together with the desensitization to Ivermectin actionin vivo by constitutively active TCF provide evidence of the specificity of this drug to block an activated WNT-TCF pathway in human cancer.
  • Ivermectin has a good safety profile since onlyin-vivo-dnTCF-sensitive cancer xenografts are responsive to Ivermectin treatment, and we have not detected side effects in Ivermectin-treated mice at the doses used
  • previous work has shown that side effects from systemic treatments with clinically relevant doses in humans are rare (Yang, 2012), that birth defects were not observed after exposure of pregnant mothers (Pacquéet al, 1990) and that this drug does not cross the blood–brain barrier (Kokozet al, 1999). Similarly, only dogs with mutantABCB1 (MDR1) alleles leading to a broken blood–brain barrier show Ivermectin neurotoxicity (Mealeyet al, 2001; Orzechowskiet al, 2012)
  • Indications may include treatment for incurable β-CATENIN/TCF-dependent advanced and metastatic human tumors of the lung, colon, endometrium, and other organs.
  • Ivermectin, Selamectin, or related macrocyclic lactones could also serve as topical agents for WNT-TCF-dependent skin lesions and tumors such as basal cell carcinomas
  • they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population
  • Nathan Goodyear on 19 Mar 18
     
    Ivermectin, a common anti-parasitic, found to inhibit WTF-TCF pathway and decrease c-terminal phosophorylaiton of Beta-CATENIN all resulting in increased aptosis and inhibition of cancer growth in colon cancer cell lines and lung cancer cell lines.
hohanbogdan

Obosit mereu - 0 views

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Sanatate

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Nathan Goodyear

Low serum albumin levels and liver metastasis are powerful prognostic markers for survi... - 0 views

onlinelibrary.wiley.com/...cncr.22300

albumin cancer liver metastasis

shared by Nathan Goodyear on 09 Jul 18 - No Cached
  • poor PS,8-10 the presence of liver metastases,7, 9, 10 and elevated LDH levels10 were independent prognostic factors
  • lymphopenia (HR of, 1.89; P = .04) and hypoalbuminemia (HR of 2.7; P < .0001) were independent prognostic factors for overall survival
  • lymphopenia in cancer patients remain unclear and may reflect in part poor nutrition
  • ...2 more annotations...
  • may result in part from the destruction of lymphocytes by the tumor and/or an impaired differentiation of lymphocytes progenitors
  • presence of liver metastasis (HR of, 2.27; P = .0003) and hypoalbuminemia were the 2 most powerful adverse prognostic factors
  • Nathan Goodyear on 09 Jul 18
     
    study finds that lympohopenia and low albumin was associated with the worse prognosis in 317 patients with liver mets with unknown primary cancer. 
Nathan Goodyear

Curcumin Inhibits Adipogenesis in 3T3-L1 Adipocytes and Angiogenesis and Obesity in C57... - 0 views

jn.nutrition.org/...919.abstract

curcumin adipogenesis obesity weight loss

shared by Nathan Goodyear on 28 Apr 11 - No Cached
  • Dietary polyphenols may suppress growth of adipose tissue through their antiangiogenic activity and by modulating adipocyte metabolism
  • curcumin, the major polyphenol in turmeric spice
  • curcumin suppression of angiogenesis in adipose tissue together with its effect on lipid metabolism in adipocytes may contribute to lower body fat and body weight gain
  • ...1 more annotation...
  • Our findings suggest that dietary curcumin may have a potential benefit in preventing obesity
  • Nathan Goodyear on 28 Apr 11
     
    Curcumin useful in obesity
Nathan Goodyear

Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer t... - 0 views

www.sciencedirect.com/...S0960977617300103

HER-2 breast cancer cancer herceptin Perjeta

shared by Nathan Goodyear on 06 Aug 18 - No Cached
  • 15%–20%
  • key mediator of cell growth, differentiation, and survival
  • of higher histological grade and are more likely to invade axillary lymph nodes
  • ...15 more annotations...
  • shortened survival and an increased risk of disease recurrence and metastasis
  • Currently, four HER2-directed agents are approved for the treatment of patients with HER2+ breast cancer: trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1)
  • biosimilars
  • trastuzumab may provide greater benefit when administered concurrently with chemotherapy rather than after, and this has become the standard approach
  • concurrent use of anthracyclines (ie, doxorubicin or epirubicin) and trastuzumab is not recommended because of an increased risk for cardiac toxicity
    • Nathan Goodyear
      Nathan Goodyear on 06 Aug 18
       
      avoid herceptin in conjuction with antracyclines i.e. doxorubicin
  • Sequential doxorubicin plus cyclophosphamide followed by concomitant paclitaxel or docetaxel and trastuzumab is recommended for most patients
    • Nathan Goodyear
      Nathan Goodyear on 06 Aug 18
       
      top recommended regimen combination
  • Guidelines also recommend trastuzumab in combination with paclitaxel, docetaxel and carboplatin, or docetaxel and cyclophosphamide, particularly for patients with increased risk for cardiac toxicity or those with small (≤1 cm), node-negative HER2+ tumors
    • Nathan Goodyear
      Nathan Goodyear on 06 Aug 18
       
      good alternative in patients with increased risk of cardiac toxicity.
  • guidelines recommend up to 1 year of adjuvant trastuzumab
  • Neoadjuvant chemotherapy with trastuzumab is associated with higher rates of pathologic complete response (pCR) than chemotherapy alone or in combination with lapatinib
  • the combination of trastuzumab, lapatinib, and chemotherapy is not recommended because it failed to demonstrate noninferiority versus trastuzumab and chemotherapy in the adjuvant setting
  • recommend the combination of trastuzumab, pertuzumab, and chemotherapy as neoadjuvant treatment for patients with locally advanced HER2+ breast cancer and for some patients (node-positive or tumor ≥2 cm) with early-stage disease
  • neoadjuvant chemotherapy in combination with pertuzumab and trastuzumab reduced the risk of progression or death by 31% and recurrence or death by 40% versus trastuzumab alone
  • Concurrent chemotherapy and HER2-directed therapy improves survival outcomes over chemotherapy alon
  • dual inhibition of HER2 with trastuzumab and pertuzumab in combination with paclitaxel reduced the risk of death or progression by approximately 40% compared with concurrent trastuzumab and paclitaxel
  • the combination of trastuzumab, pertuzumab, and taxane chemotherapy is the preferred first-line regimen
  • Nathan Goodyear on 06 Aug 18
     
    HER-2 + breast cancer = appx 15-20% of all breast cancers and is a marker of worse prognosis and an indication for targeted immunotherapy blockade.
Nathan Goodyear

From the Cover: Pharmacologic doses of ascorbate act as a prooxidant and decrease growt... - 0 views

www.ncbi.nlm.nih.gov/...PMC2516281

cancer IV intravenous vitamin C IV vitamin C

shared by Nathan Goodyear on 18 Sep 13 - No Cached
  • An extensive panel of 43 tumor and 5 normal cell lines were exposed to ascorbate in vitro for ≤2 h to mimic clinical pharmacokinetics
  • effective concentration that decreased survival 50% (EC50) was determined. EC50 was <10 mM for 75% of tumor cells tested, whereas cytotoxicity was not evident in normal cells with >20 mM ascorbate
  • The addition of catalase to the medium ameliorated death of ovarian carcinoma (Ovcar5), pancreatic carcinoma (Pan02), and glioblastoma (9L) cells exposed to 10 mM ascorbate (1 h), indicating cytotoxicity was mediated by H2O2
  • ...8 more annotations...
  • A treatment dose of 4 g ascorbate/kg body weight either once or twice daily did not produce any discernible adverse effects
  • Xenograft experiments showed that parenteral ascorbate as the only treatment significantly decreased both tumor growth and weight by 41–53%
  • Peak plasma concentrations of ascorbate approached 30 mM
  • Pharmacologic concentrations of ascorbate decreased tumor volumes 41–53% in diverse cancer types known for both their aggressive growth and limited treatment options.
  • Our findings showed that pharmacologic ascorbic acid concentrations were cytotoxic to many types of cancer cells in vitro (Fig. 1A) and significantly impeded tumor progression in vivo without toxicity to normal tissues
  • The amelioration of ascorbate cytotoxicity in vitro by the addition of catalase was consistent among sensitive cancer cells (Fig. 1B) and points unambiguously to H2O2 generation in the extracellular medium
  • the current in vivo data support that pharmacologic ascorbate concentrations, which can readily be achieved in humans (Fig. 3E), diminished growth of several aggressive cancer types in mice (Fig. 2) without causing apparent adverse effects.
  • These intratumoral H2O2 concentrations of >125 μM persisted for >3 h after ascorbate administration
  • Nathan Goodyear on 18 Sep 13
     
    Tumor xenograft model in mice finds reduction in growth rates of ovarian cancer, pancreatic cancer, and glioblastoma with daily IV vitamin C.
Nathan Goodyear

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and p... - 0 views

www.ncbi.nlm.nih.gov/...PMC3706910

progesterone metabolites metabolite 5-alpha pregnene 5-alpha pregnenes 5alpha-dihydroprogesterone 4-pregnene 4-pregnenes 3alpha-dihydroprogesterone breast cancer ER PR hormone hormones receptors estrogen

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
  • Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
  • When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
  • ...31 more annotations...
  • Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
  • Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
  • The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
  • hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
  • a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative
  • about 90% of normal proliferating breast epithelial cells are receptor negative
  • Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure ​(Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
  • The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
  • In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
  • the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
  • Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
  • The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
  • The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
  • In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
  • When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
  • The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
  • Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
  • ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
  • 3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
  • serum from mice with tumors had significantly more 5αP than 3αHP
  • the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and >10-fold higher 5αP than 3αHP levels
  • Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
  • Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
  • breast carcinomas are able to synthesize progesterone
  • The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
  • Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
  • 5α-reductase and 5αPR levels are upregulated by 5αP
  • in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
  • the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
  • because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
  • The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
  • Nathan Goodyear on 28 Jan 14
     
    Progesterone metabolites and breast cancer
Nathan Goodyear

Branched-chain amino acids and muscle ammoni... [Metab Brain Dis. 2013] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23315357

NH3 muscle brain urea cycle metabolism BCAA branched chain amino acids liver cirrhosis disease

shared by Nathan Goodyear on 10 Feb 14 - No Cached
  • BCAA metabolism may improve muscle net ammonia removal by supplying carbon skeletons for formation of alfa-ketoglutarate that combines with two ammonia molecules to become glutamine
  • Nathan Goodyear on 10 Feb 14
     
    Muscle becomes the primary mode of NH3 metabolism in liver cirrhosis.  The authors here propose that it is via an increase in muscle mass rather than specifically lowering NH3.  In fact, there is an early increase in NH3 production.
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