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Nathan Goodyear

T cells in systemic sclerosis: a reappraisal. - ResearchGate - 0 views

www.researchgate.net/...stemic_sclerosis_a_reappraisal

scleroderma IL-6 autoimmune disease cytokines

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Nathan Goodyear on 22 Jan 14
     
    Article looks at the role of IL-6 in fibrosis in scleroderma.  The fibrosis in scleroderma appears to be a Th2 driven process.
Nathan Goodyear

Curcumin suppresses TGF-β signaling by inhibition of TGIF degradation in scle... - 0 views

www.sciencedirect.com/...S0006291X11012630

curcumin tumeric scleroderma autoimmune disease TGF-beta inflammation

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Nathan Goodyear on 22 Jan 14
     
    Curcumin reduces fibrosis in scleroderma via TGF-beta inhibition.  TGF-beta plays an important role in the fibrosis in scleroderma.
Nathan Goodyear

Curcumin & Liver Fibrosis Focused Research | GreenMedInfo.com - 0 views

www.greenmedinfo.com/...page

curcumin curcuma longa turmeric liver liver disease

shared by Nathan Goodyear on 06 Jul 16 - No Cached
  • Nathan Goodyear on 06 Jul 16
     
    33 studies that highlight the benefit of curcumin in liver fibrosis.
Nathan Goodyear

Effect of melatonin on normal and... [Clin Exp Rheumatol. 1996 Sep-Oct] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...8913650

melatonin fibrosis scleroderma autoimmune disease

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Nathan Goodyear on 22 Jan 14
     
    Melatonin inhibits fibrosis.
Nathan Goodyear

Effects of potassium para-aminobenzoate on... [J Invest Dermatol. 1979] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...155125

scleroderma fibrosis PABA autoimmune disease

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Nathan Goodyear on 22 Jan 14
     
    PABA at high doses shown to reduce fibrosis in those with scleroderma.
Nathan Goodyear

Modulation of Fibrosis in Systemic Sclerosis by Nitric Oxide and Antioxidants - 0 views

www.hindawi.com/...521958

scleroderma EGCG epigallocatechin-3-gallate green tea autoimmune disease oxidative stress sclerosis inflammation antioxidants

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  • Nathan Goodyear on 22 Jan 14
     
    Animal and human study finds protection against fibrosis with EGCG in those with scleroderma.
Nathan Goodyear

Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxid... - 0 views

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

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

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

[Madecassol treatment of systemic and localized scl... [Ter Arkh. 1998] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...9644746

Gotu kola scleroderma inflammation autoimmune disease Centella asiatica

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Nathan Goodyear on 22 Jan 14
     
    Gotu kola found to benefit the fibrosis in scleroderma both via oral and topical dosing.
Nathan Goodyear

Serum 25OH vitamin D concentrations are linked with various clinical aspects in patient... - 0 views

www.researchgate.net/...y_and_review_of_the_literature

vitamin d vitamin D scleroderma autoimmune disease

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  • Nathan Goodyear on 22 Jan 14
     
    Vitamin D levels inversely associated with fibrosis in scleroderma.
Nathan Goodyear

http://rheumatology.oxfordjournals.org/content/49/11/2024.full.pdf - 0 views

rheumatology.oxfordjournals.org/...2024.full.pdf

EGCG epigallocatechin-3-gallate green tea NF-kappaB inflammation scleroderma autoimmune disease

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Nathan Goodyear on 22 Jan 14
     
    EGCG found to reduce extra cellular matrix production, fibrosis, and NF-kappaB activity in those with scleroderma.
Nathan Goodyear

Marathons damage the hearts of less fit runners for up to three months - - Heart and St... - 0 views

www.heartandstroke.nb.ca/...content2.aspx

endurance training running runners marathon marathons heart health CVD exercise

shared by Nathan Goodyear on 09 Jan 15 - No Cached
  • Nathan Goodyear on 09 Jan 15
     
    Summary of 2010 report on marathons and the heart.  Less fit runners can do significant damage to the heart i.e. fibrosis compared to fit runners.  V02 max is a good way to assess aerobic endurance and differentiate between the two.  Dr Larose showed via MRI that it can take 3 months for the heart to recover.
Nathan Goodyear

Exercise-induced right ventricular dysfunction and structural remodelling in endurance ... - 0 views

eurheartj.oxfordjournals.org/...998

endurance athletes training heart health injury

shared by Nathan Goodyear on 09 Jan 15 - No Cached
  • In a cohort of well-trained athletes, we demonstrated that intense endurance exercise causes an acute reduction in RV function that increases with race duration and correlates with increases in biomarkers of myocardial injury
  • no relationship between LV function and biomarker levels
  • focal gadolinium enhancement and increased RV remodelling were more prevalent in those athletes with a longer history of competitive sport, suggesting that repetitive ultra-endurance exercise may lead to more extensive RV change and possible myocardial fibrosis
  • ...22 more annotations...
  • he cardiac impact of both acute and cumulative exercise is greatest on the RV.
  • Greater reductions in RV function occurred in those athletes competing for a longer duration, suggesting that the heart has a finite capacity to maintain the increased work demands of exercise
  • cardiac injury is greatest in the least trained
  • Previous investigators have documented reductions in RV function in less trained subjects over the marathon distance
  • We enrolled elite and subelite athletes and found a significant association between fitness (VO2max) and the reduction in post-race RVEF
  • Even after many years of detraining, cardiac dilation may not completely regress in elite athletes
  • The focus on well-trained athletes may be of particular relevance, given that they perform exercise of highest intensity and duration most frequently, and, thus, may be at a greater risk of cumulative injury.
  • The lack of correlation between increases in troponin and changes in LV function seen in this study has been previously interpreted as evidence that post-exercise elevations in cardiac biomarkers are benign.
  • a significant correlation between changes in RVEF and post-race biomarker levels and this relationship was even stronger in the athletes who completed the race of longest duration, the ultra-triathlon
  • The correlations with RVEF, but not LVEF, provide further evidence of the differential effects of intense exercise on RV and LV function
  • BNP release during intense exercise is associated with greater relative increases in RV systolic pressures, but not LV pressures
  • BNP may provide a measure of both acute RV load and the resultant fatigue which occurs when this load is sustained
  • It has been demonstrated that ventricular load increases with exercise intensity and is greater for the RV than the LV,29 thus potentially explaining why the RV is more susceptible to fatigue after prolonged exercise.
  • This study demonstrates, for the first time, an association between endurance exercise of increasing duration and structural, functional, and biochemical markers of cardiac dysfunction in highly trained athletes
  • Functional abnormalities were confined to the RV and were largely reversible 1 week following the event
  • there remained a significant minority of athletes in whom there was evidence of myocardial fibrosis in the interventricular septum
  • RV abnormalities may be acquired through cumulative bouts of intense exercise and provides direction for prospective investigations aimed at elucidating whether extreme exercise may promote arrhythmias in some athletes.
  • the acute injury and chronic remodelling of the myocardium both disproportionately affect the RV and it remains possible that the two are linked.
  • focal DGE was confined to the interventricular septum and commonly at the site of RV attachment
  • emerging evidence that intense endurance exercise may be associated with an excess in arrhythmic disorders, the mechanisms for which remain unexplained
  • RVEF (and not LVEF) was reduced in athletes with complex ventricular arrhythmias when compared with healthy athletes and non-athletes without arrhythmias
  • it is premature to conclude that these changes may represent a proarrhythmic substrate
  • Nathan Goodyear on 09 Jan 15
     
    Study finds endurance racing results in reduce Right ventricle ejection fraction even in elite athletes.  This post-race RVEF reduction is associated with VO2max.
star yu

Son Riñones Self Healing para la Enfermedad Renal Crónica - 0 views

www.hospitalrenal.com/...583.html

enfermedad renal crónica tratamiento

shared by star yu on 08 Mar 15 - No Cached
  • star yu on 08 Mar 15
     
    Sabes, algunos tejidos del cuerpo humano pueden curarse a sí mismos, por ejemplo, la fibrosis hepática y la cirrosis hepática es las manifestaciones patológicas de la regeneración hepática y reparación Sabes, algunos tejidos del cuerpo humano pueden curarse a sí mismos, por ejemplo, la fibrosis hepática y la cirrosis hepática es las manifestaciones patológicas de la regeneración hepática y reparación.Entonces, para los pacientes con enfermedad renal crónica, son los riñones auto sanación?
Nathan Goodyear

American Journal of Obstetrics & Gynecology Home Page - 0 views

www.ajog.org/...fulltext

"Vaginal mesh" immune system

shared by Nathan Goodyear on 31 Aug 18 - No Cached
  • M1 macrophages are characterized by the secretion of reactive oxygen species and proinflammatory cytokines and chemokines and can be identified via the cell surface marker CD86
  • M2 macrophages secrete growth factors and antiinflammatory immune modulators and can be identified by the cell surface marker CD206
  • an overzealous M2 response can also lead to excess tissue deposition and fibrosis
  • ...14 more annotations...
  • Studies of similar meshes that are used in hernia repair have demonstrated that all polypropylene meshes induce a prolonged inflammatory response at the site of implantation
  • the long-term presence of activated inflammatory cells, such as macrophages at the mesh tissue interface, can impact negatively the ability of the mesh to function as intended.
  • All M1 proinflammatory and M2 proremodeling cytokines and chemokines were increased in mesh explants as compared with nonmesh tissue (Table 3Table 3), which indicated a robust, active, and ongoing host response to polypropylene long after implantation
  • Comparison of the ratio of the M2 proremodeling cytokines (IL-10+IL-4) with the M1 proinflammatory cytokines (TNF-α+IL-12p70) revealed a decrease in mesh explants as compared with controls (P = .003), which indicated a shift towards a proinflammatory profile.
  • Mesh explants contained a higher number of total cells/×200 field when compared with controls (682.46 ± 142.61 cells vs 441.63 ± 126.13 cells; P < .001) and a lower ratio of M2:M1 macrophages (0.260 ± 0.161 cells vs 1.772 ± 1.919; P = .001), which supported an ongoing proinflammatory response.
  • the host response was proportional to the amount of material in contact with the host
  • A persistent foreign body response was observed in mesh-tissue complexes that were excised from women who required surgical excision of mesh months to years after mesh implantation
  • The host response was characterized by a predominance of macrophages with an increase in both proinflammatory and proremodeling cytokines/chemokines along with increased tissue degradation, as evidenced by increased MMP-2 and -9
  • Mesh-tissue complexes removed for mesh exposure had increased pro–MMP-9 that indicated a proinflammatory and tissue destruction–type response
  • The presence of macrophages, elevated cytokines, chemokines, and MMPs in tissue-mesh complexes that were excised from patients with exposure or pain suggests that polypropylene mesh elicits an ongoing host inflammatory response
  • In the presence of a permanent foreign body, the implant is surrounded with a fibrotic capsule because it cannot be degraded
  • For hernia meshes, if the fibers are too close (<1 mm), the fibrotic response to neighboring fibers overlaps, or “bridges,” and results in “bridging fibrosis” or encapsulation of the mesh
  • Gynemesh PS has a highly unstable geometry when loaded that resulted in pore collapse and increasing stiffness of the product
  • mesh shrinkage (50-70%) has been described to occur after transvaginal insertion of prolapse meshes
  • Nathan Goodyear on 31 Aug 18
     
    Mesh and the abnormal immune response.
Nathan Goodyear

Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865785/ - 0 views

www.ncbi.nlm.nih.gov/...PMC4865785

CF cystic fibrosis

shared by Nathan Goodyear on 07 Feb 17 - No Cached
  • Nathan Goodyear on 07 Feb 17
     
    good review of CF
Nathan Goodyear

Cytokine profiles in localized scleroderma and relationship to clinical features - 0 views

www.ncbi.nlm.nih.gov/...PMC3632442

morphea autoimmune disease children scleroderma inflammation

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Evaluation of the literature reveals a Th2 predominant cytokine profile in the biological specimens (sera, PBMCs, and tissue) of those with SSc
  • the literature available from studies in LS show that Th1, Th2, and Th17 cytokines may contribute equally to the pathogenesis of the disease
  • Classically, Th1 cells have been known to secrete IL-2, IFN-γ, and TNF-α, and are stimulated by IL-2 and IL-12
  • ...3 more annotations...
  • Th2 cells have been shown to be activated by IL-4 and produce IL-4, IL-5, IL-10 and IL-13
  • Th17 cells, a more recently identified Th cell subset that has altered the classic Th1/Th2 paradigm, produce IL-17 A/F, IL-21, and IL-22. IL-1, IL-6, IL-23, and TGF-β are now known to play important roles in the differentiation and propagation of the Th17 cell lineage
  • there is an overall notion that pro-inflammatory Th1 and Th17 associated cytokines are elevated during the early stages of scleroderma, whereas Th2 cytokines mainly correlate with disease damage and fibrosis extent
  • Nathan Goodyear on 22 Jan 14
     
    morphea
Nathan Goodyear

Curcumin-induced apoptosis in scleroderma lung fibroblasts - Role of protein kinase Cep... - 0 views

eurekamag.com/...of-protein-kinase-cepsilon.php

curcumin tumeric autoimmune disease scleroderma fibrosis

shared by Nathan Goodyear on 22 Jan 14 - No Cached
  • Nathan Goodyear on 22 Jan 14
     
    Curcumin found to cause apoptosis of fibrotic pulmonary cells versus no effect on healthy pulmonary cells.
Nathan Goodyear

Oral antibiotics for treating infection with Pseudomonas aeruginosa in people with cyst... - 0 views

www.ncbi.nlm.nih.gov/...PMH0013450

P aeruginosa treatment pseudomonas aeruginosa

shared by Nathan Goodyear on 30 Sep 14 - No Cached
  • Nathan Goodyear on 30 Sep 14
     
    Oral Antibiotics, no less effective than IV therapy.  This is a cochrane review of the treatment of p aeruginosa in those with CF.
Nathan Goodyear

http://www.msma.org/docs/communications/momed/Excessive_Endurance_Exercise_and_Heart_Di... - 0 views

www.msma.org/..._Disease_MOMED_JulyAug2012.pdf

heart disease endurance exercise exercise marathons triathlon endurance athletes heart health disease

shared by Nathan Goodyear on 10 Jan 15 - No Cached
  • Nathan Goodyear on 10 Jan 15
     
    great review of data on cardiac damage associated with extreme endurance training.  These EEEs, that they are called, are rare in those < 40 and usually involved genetic defects.  This article points to aggressive preventive testing in those > 50.
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