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Nathan Goodyear

Medical education in pharmacogenomics-results from a survey on pharmacogenetic knowledge in healthcare professionals within the European pharmacogenomics clinical implementation project Ubiquitous Pharmacogenomics (U-PGx) - 0 views

www.ncbi.nlm.nih.gov/...PMC5599468

genetics pharmacogenetics

shared by Nathan Goodyear on 17 Jan 18 - No Cached
  • Of participants, 84.3% found pharmacogenomics relevant to their current practice
  • More than two-thirds (65.7%) did not order nor recommend a pharmacogenomic test in the past year
  • pharmacogenomic testing was understood mainly for assessment of the variability of genes affecting drug disposition, metabolism and drug transport leading to individual responses to drugs
  • ...4 more annotations...
  • Pre-emptive, prospective, genotyping to make individualised drug therapy feasible is seen to contribute to personalised medicine
  • assumed to improve drug efficacy and safety
  • Potential benefits of pharmacogenomics (PGx) have been defined such as predicting intended response to medication by more accurate dosing, avoiding adverse drug reactions and therefore enhancing drug safety and reducing health care cost
  • survey among Dutch pharmacists revealed 14.7% recent users of PGx diagnostics [27], whereas in our cohort, the percentage was with 34.3% higher.
  • Nathan Goodyear on 17 Jan 18
     
    Doctors and pharmacists are slow to integrate pharmacogenetics. Good working definition of pharmacogenetics as well.
Nathan Goodyear

Demystified . . . Human endogenous retroviruses - 0 views

www.ncbi.nlm.nih.gov/...PMC1187282

HERV retroviruses human endogenous retroviruses

shared by Nathan Goodyear on 14 May 18 - No Cached
  • HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits
  • However, several HERVs have been implicated in certain cancers and autoimmune diseases
  • HERVs constitute about 1% of the human genome
  • ...16 more annotations...
  • Human endogenous retroviruses (HERVs) represent footprints of previous retroviral infection and have been termed “fossil viruses”
  • HERVs possess a similar genomic organisation to present day exogenous retroviruses such as human immunodeficiency virus (HIV) and human T cell leukaemia virus (HTLV)
  • Retroviruses in effect are retrograde, because the flow of genetic information is reversed compared with the normal pathway of molecular biosynthesis—DNA → RNA → protein. Indeed, all retroviruses necessitate the conversion of viral RNA into a cDNA intermediary, which is catalysed by the enzyme reverse transcriptase
  • Overall, human endogenous retroviruses constitute about 1% of the human genome”
  • some HERVs have been implicated in certain autoimmune diseases and cancers
  • A unit of sugar, phosphate, and base is strictly termed a nucleotide
  • human genes are composed of exons, which are transcribed and translated into amino acids
  • introns, which are interspersed between exons and represent non-translated regions that contribute to the large size of some genes
  • convincing argument for the possible involvement of HERVs in malignancy
  • HERVs may be involved in carcinogenesis by virtue of the expression of HERV mRNA,26 functional proteins,27 or retroviral-like particles
  • They may also be associated with the generation of new promoters29 or the activation of proto-oncogenes
  • inhibition of an effective immune response,
  • encode immunosuppressive proteins
  • “It has been suggested that HERV-K may be important in the progression of testicular germ cell tumours through inhibition of an effective immune response”
  • HERV-K might be important in the pathogenesis of human breast cancer
  • activation of proto-oncogenes of the ras family is common in many tumour types, and some studies have suggested a potential role for HERVs in ras activation
  • Nathan Goodyear on 14 May 18
     
    good review of HERVs.
Nathan Goodyear

Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for Non-Small Cell Lung Cancer | Scientific Reports - 0 views

www.nature.com/...srep13110

PD-1 cancer check point inhibitors PD-L1 CLTA-4 immunotherapy

shared by Nathan Goodyear on 20 Apr 18 - No Cached
  • the lack of immunologic control is recognized as a hallmark of cancer currently
  • Programmed death-1 (PD-1) and its ligand PD-L1 play a key role in tumor immune escape and the formation of tumor microenvironment, closely related with tumor generation and development
  • Blockading the PD-1/PD-L1 pathway could reverse the tumor microenvironment and enhance the endogenous antitumor immune responses.
  • ...4 more annotations...
  • environmental factors, living habits, genetic mutations, dysfunction of the immune system and so on
  • special tumor immune microenvironment
  • cytotoxic T lymphocyte-associated antigen 4 (CLTA-4), Programmed death-1 (PD-1) and its ligands PD-L1 (B7H1) and PD-L2 (B7-DC)
  • CTLA-4 regulates T cell activity in the early stage predominantly, and PD-1 mainly limits the activity of T-cell in the tumor microenvironment at later stage of tumor growth
  • Nathan Goodyear on 20 Apr 18
     
    PD-1 to read.
Nathan Goodyear

Cancer Genome Landscapes - 0 views

www.ncbi.nlm.nih.gov/...PMC3749880

genetics cancer

shared by Nathan Goodyear on 13 Aug 19 - No Cached
  • Nathan Goodyear on 13 Aug 19
     
    To be read
fnfdoc

Psoriasis: Causes, Symptoms, Types & Treatment - Health Blog - 0 views

fnfdoc.com/auses-symptoms-types-treatment

Psoriasis Psoriasis Causes Psoriasis Symptoms Psoriasis Types Psoriasis Treatment Common Causes Of Psoriasis Most Common Causes Of Psoriasis Genetics and Psoriasis Microbes And Psoriasis Key Signs And Symptoms Of Psoriasis Diagnose Psoriasis Most Popular

shared by fnfdoc on 11 Apr 20 - No Cached
  • fnfdoc on 11 Apr 20
     
    Psoriasis is a chronic skin condition that accelerates the rate at which your skin cells grow. An effective method to treat psoriasis is phototherapy or light therapy.
  • fnfdoc on 11 Apr 20
     
    Psoriasis is an auto-immune illness that affects almost three percent of the world's population. People who suffer from psoriasis experience a great deal of skin irritation and discomfort.
Nathan Goodyear

Histamine and histamine intolerance - 0 views

ajcn.nutrition.org/...1185.long

histamine histamine intolerance DAO diamine oxidase HNMT methylation

shared by Nathan Goodyear on 24 Mar 15 - No Cached
  • Histamine intolerance can develop through both increased availability of histamine and impaired histamine degradation
  • increased availability may be an endogenous histamine overproduction caused by allergies, mastocytosis, bacterias, gastrointestinal bleeding, or increased exogenous ingestion of histidine or histamine by food or alcohol
  • Other biogenic amines, such as putrescine, may also be involved in displacing histamine from its mucosal mucine linkage, which results in an increase of free absorbable histamine in circulation
  • ...2 more annotations...
  • the main cause of histamine intolerance is an impaired enzymatic histamine degradation caused by genetic or acquired impairment of the enzymatic function of DAO or HNMT
  • The main enzyme for metabolism of ingested histamine is diamine oxidase (DAO)
  • Nathan Goodyear on 24 Mar 15
     
    good discussion of histamine and histamine intolerance.  All centers around diamine oxidase function (DAO).
Nathan Goodyear

Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes - 0 views

www.ncbi.nlm.nih.gov/...PMC3501844

exercise diabetes epigenetics muscle mitochondria VO2max

shared by Nathan Goodyear on 03 Oct 17 - No Cached
  • epigenetic modifications of single genes have been shown to affect the pathogenesis of T2D
  • An FH of T2D is an independent predictor of future risk for the disease
  • exercise for 6 months is associated with epigenetic changes, e.g., decreased DNA methylation of RUNX1 and MEF2A, two key transcription factors involved in exercise training (42–44), of THADA, previously associated with T2D (1), and of NDUFC2, which is part of the respiratory chain (45) was observed after exercise
  • ...4 more annotations...
  • exercise changed both DNA methylation and expression of a number of genes, including ADIPOR1, ADIPOR2, and BDKRB2, encoding receptors for adiponectin and bradykinin, respectively, which both regulate metabolism in muscle
  • we cannot draw a conclusion as to whether differential expression is a consequence rather than a cause of changes in methylation
  • ageing is associated with increased DNA methylation and decreased expression of genes involved in oxidative phosphorylation in human muscle
  • exercise can induce genome-wide epigenetic changes in human muscle and that the response may differ in people with different genetic predispositions to metabolic disease
  • Nathan Goodyear on 03 Oct 17
     
    Six months of exercise induce epigenetic changes through decrease in methylation.  This study was designed to look at those with a family risk of DM.  They found a difference in the methylation status of muscle between those with a family h/o diabetes and those without.  This would have implications in therapeutic difference prior to diagnosis.  Even a increased VO2max and skeletal muscle mitochondrial density was found to be the result of decreased methylation of the NDUFC2 gene after exercise.
Nathan Goodyear

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal - 0 views

www.hindawi.com/...360438

MDA malondialdehyde peroxidation oxidative stress free radicals

shared by Nathan Goodyear on 05 Dec 17 - No Cached
  • Hydroxyl radicals cause oxidative damage to cells because they unspecifically attack biomolecules [22] located less than a few nanometres from its site of generation and are involved in cellular disorders such as neurodegeneration [23, 24], cardiovascular disease [25], and cancer [26, 27].
  • It is generally assumed that in biological systems is formed through redox cycling by Fenton reaction, where free iron (Fe2+) reacts with hydrogen peroxide (H2O2) and the Haber-Weiss reaction that results in the production of Fe2+ when superoxide reacts with ferric iron (Fe3+)
  • other transition-metal including Cu, Ni, Co, and V can be responsible for formation in living cells
  • ...20 more annotations...
  • The hydroperoxyl radical () plays an important role in the chemistry of lipid peroxidation
  • The is a much stronger oxidant than superoxide anion-radical
  • Lipid peroxidation can be described generally as a process under which oxidants such as free radicals or nonradical species attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs) that involve hydrogen abstraction from a carbon, with oxygen insertion resulting in lipid peroxyl radicals and hydroperoxides as described previously
  • under medium or high lipid peroxidation rates (toxic conditions) the extent of oxidative damage overwhelms repair capacity, and the cells induce apoptosis or necrosis programmed cell death
  • The overall process of lipid peroxidation consists of three steps: initiation, propagation, and termination
  • Once lipid peroxidation is initiated, a propagation of chain reactions will take place until termination products are produced.
  • The main primary products of lipid peroxidation are lipid hydroperoxides (LOOH)
  • Among the many different aldehydes which can be formed as secondary products during lipid peroxidation, malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal (4-HNE) have been extensively studied
  • MDA has been widely used for many years as a convenient biomarker for lipid peroxidation of omega-3 and omega-6 fatty acids because of its facile reaction with thiobarbituric acid (TBA)
  • MDA is one of the most popular and reliable markers that determine oxidative stress in clinical situations [53], and due to MDA’s high reactivity and toxicity underlying the fact that this molecule is very relevant to biomedical research community
  • 4-HNE is considered as “second toxic messengers of free radicals,” and also as “one of the most physiologically active lipid peroxides,” “one of major generators of oxidative stress,” “a chemotactic aldehydic end-product of lipid peroxidation,” and a “major lipid peroxidation product”
  • MDA is an end-product generated by decomposition of arachidonic acid and larger PUFAs
  • Identifying in vivo MDA production and its role in biology is important as indicated by the extensive literature on the compound (over 15 800 articles in the PubMed database using the keyword “malondialdehyde lipid peroxidation” in December 2013)
  • MDA reactivity is pH-dependent
  • When pH decreases MDA exists as beta-hydroxyacrolein and its reactivity increases
  • MAA adducts are shown to be highly immunogenic [177–181]. MDA adducts are biologically important because they can participate in secondary deleterious reactions (e.g., crosslinking) by promoting intramolecular or intermolecular protein/DNA crosslinking that may induce profound alteration in the biochemical properties of biomolecules and accumulate during aging and in chronic diseases
  • MDA is an important contributor to DNA damage and mutation
  • This MDA-induced DNA alteration may contribute significantly to cancer and other genetic diseases.
  • Dietary intake of certain antioxidants such as vitamins was associated with reduced levels of markers of DNA oxidation (M1dG and 8-oxodG) measured in peripheral white blood cells of healthy subjects, which could contribute to the protective role of vitamins on cancer risk
  • 4-HNE is an extraordinarily reactive compound
  • Nathan Goodyear on 05 Dec 17
     
    Great review of lipid peroxidation
Nathan Goodyear

Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras | Nature Communications - 0 views

www.nature.com/...s41467-017-01019-z

cancer glucose sugar nutrition genetics vitamin C RAS

shared by Nathan Goodyear on 20 Oct 17 - No Cached
  • glucose deprivation triggers apoptosis47 and vitamin C treatment kills RAS-oncogene expressing tumor cells, but not wild-type RAS containing cells, by inhibition of GAPDH
  • Nathan Goodyear on 20 Oct 17
     
    New study out of the UK supports the role of glucose in cancer growth and aggressiveness.  This research found that high influx of glucose into the glycolysis pathway upregulated the RAS oncogene via accumulation of the Fructose 1,6 bisphosphonate through the enzyme phosphofructokinase..
Nathan Goodyear

Antioxidant vitamins intake, ataxia telangiectasia mutated (ATM) genetic polymorphisms, and breast cancer risk - PubMed - 0 views

pubmed.ncbi.nlm.nih.gov/21058196

ATM breast cancer vitamin C vitamin A

shared by Nathan Goodyear on 24 May 21 - No Cached
  • Nathan Goodyear on 24 May 21
     
    ATM in breast cancer associated with low vitamin A and C levels.
Nathan Goodyear

Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation - 0 views

www.ncbi.nlm.nih.gov/...PMC5282724

EMT TME metastasis cancer stem cells cancer MMP2 Notch MMP-9 MMP-2 radioresistance Hedgehog CSC MMP9 Snail HIF-1alpha tumor microenvironment epithelial to mesenchymal transition TGF-beta radiation

shared by Nathan Goodyear on 09 Feb 21 - No Cached
  • More than half of cancer patients are treated with IR at some point during their treatment
  • fractionation schedule is the delivery of 1.8–2.0 Gy per day, five days per week
  • Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
  • ...121 more annotations...
  • IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production
  • IR is known to induce EMT in vitro
  • p53 is activated in response to IR-induced DNA damage
  • IR paradoxically also promotes tumour recurrence and metastasis
  • DNA double-strand breaks (DSBs)
  • cancer cells undergoing EMT acquire invasive and metastatic properties
  • changes in the tumour microenvironment (TME)
  • IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism
  • EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
  • Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
  • EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
  • IR is known to induce stemness and metabolic alterations in cancer cells
  • transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
  • activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
  • Loss of E-cadherin is considered a hallmark of EMT
  • IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
  • IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
  • sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
  • ROS are known to play an important role in IR-induced EMT
  • High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
  • hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT
  • Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      NAC for all patients receiving radiation therapy
  • Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion
  • IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
  • NF-κB signalling that promotes cell migration
  • ROS promote EMT to allow cancer cells to avoid hostile environments
  • HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
  • Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
  • levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
  • IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
  • IR induces vascular damage that causes hypoxia
  • ROS is implicated in IR-induced HIF-1 activation
  • IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
  • IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
  • The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
  • TGF-β signalling has been shown to play a crucial role in IR-induced EMT
  • AP-1 transcription factor is involved in IR-induced TGF-β1 expression
  • Wnt/β-catenin signalling is also implicated in IR-induced EMT
  • Notch signalling is known to be involved in IR-induced EMT
  • IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail
  • PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
  • EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
  • ROS and RNS are also implicated in IR-induced EGFR activation
  • IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT
  • IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
  • CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
  • Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
  • identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
  • CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
  • Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,
  • signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
  • microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451
  • Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes
  • EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
  • Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
  • TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
  • some CSC subpopulations arise independently of EMT
  • IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
  • Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
  • IR has been shown to induce reprogramming of differentiated cancer cells into CSCs
  • In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
  • IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
  • EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
  • STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
  • Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
  • metabolic reprogramming
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • metabolic reprogramming
  • tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis
  • occurring within the same tumour
  • CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen
  • mitochondrial function is crucial for maintaining CSC functionality
  • cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
  • HIF-1 then enhances glycolysis
  • CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
  • lactate transporter, monocarboxylate transporter (MCT)
  • nutrient microenvironment
  • Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
  • MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
  • metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
  • bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
  • the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
  • HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
  • HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
  • STAT3 has been implicated in EMT-induced metabolic changes as well
  • TGF-β and Wnt play important roles in the metabolic alteration of cancer cells
  • Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness
  • EMT, invasion, metastasis, and stemness
  • pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
  • decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis
  • LDH catalyses the bidirectional conversion of lactate to pyruvate
  • High levels of LDHA are positively correlated with the expression of EMT and CSC markers
  • IR has been shown to induce metabolic changes in cancer cells
  • IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
  • IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
  • IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
  • IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
  • Lactate can activate latent TGF-
  • lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
  • promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
  • tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
  • immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
  • immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
  • intrinsic immunogenicity or induce tolerance
  • cancer immunoediting’
  • three phases: 1) elimination, 2) equilibrium, and 3) escape.
  • The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
  • IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
  • IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
  • TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      And now the receipts
  • MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      Receipts and mechanisms
  • IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis
  • IR-induced Snail increases MMP-2 expression to promote EMT
  • Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness
  • IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
  • Metabolic alterations
  • oncogenic metabolism
  • elicit various changes in the TME
  • Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
  • Nathan Goodyear on 09 Feb 21
     
    Important review article.
Nathan Goodyear

Redox regulation in cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC2835886

estrogen cancer stem cells reaction" CSC hormones cancer Redox

shared by Nathan Goodyear on 08 Nov 18 - No Cached
  • Mitochondrial electron-transport chain and other oxidizing agents are the prime pathways that generate excess ROS in vivo
  • Permanent modification of genetic material resulting from the oxidative damage is one of the vital steps involved in mutagenesis that leads to carcinogenesi
  • The most frequent DNA mutations caused during oxidative stress, initiated by ionizing radiation and other environmental carcinogens are 7,8-dihydro-8-oxoguanine (8-Oxo-G) and Thymine Glycol (TG)
  • ...3 more annotations...
  • catalase and SOD, GPx, GST
  • insulin like growth factor I, or fibroblast growth factor 2 generates ROS
  • Depletion of GSH increases the sensitivity of cells to ROS
  • Nathan Goodyear on 08 Nov 18
     
    The redox reaction in cancer: great read!
Nathan Goodyear

Genetically targeted fractionated chemotherapy - 0 views

chemotherapy cancer fractionated chemotherapy low-dose chemotherapy insulin

shared by Nathan Goodyear on 03 Jul 20 - No Cached
  • Nathan Goodyear on 03 Jul 20
     
    Good article review on low-dose or fractionated chemotherapy.
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