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Nathan Goodyear

Surgical oncotaxis--excessive surgical stress and postoperative complications contribut... - 0 views

pubmed.ncbi.nlm.nih.gov/15788961

cytokine storm oncotaxis surgical oncotaxis

shared by Nathan Goodyear on 09 Dec 21 - No Cached
  • Nathan Goodyear on 09 Dec 21
     
    Surgical oncotaxis induced via cytokine storm.
Nathan Goodyear

Immunonutrition in Surgical Patients: Ingenta Connect - 0 views

www.ingentaconnect.com/...art00009

surgery nutrition malnutrition IV nutrition IV therapy inflammation oxidative stress

shared by Nathan Goodyear on 13 Jul 17 - No Cached
  • Nathan Goodyear on 13 Jul 17
     
    Malnutrition is associated with increased surgical risk and poor outcomes. The authors support IV preoperative nutrition at least 10 days prior to surgery and for 7 days post surgery.  This therapy reduced inflammation and oxidative stress.
Nathan Goodyear

ingentaconnect Immunonutrition in Surgical Patients - 0 views

www.ingentaconnect.com/...art00009

immunonutrition surgery surgical patients

shared by Nathan Goodyear on 21 Mar 11 - No Cached
  • Surgery induces an inflammatory response
  • A range of nutrients, including several amino acids, antioxidant vitamins and minerals, ω-3 fatty acids, and nucleotides, are able to modulate inflammation and the associated oxidative stress, and maintain or improve immune function
  • parenteral glutamine is recommended in patients receiving parenteral nutrition
  • ...2 more annotations...
  • Antioxidants, particularly selenium, should be considered for critically ill patients
  • enteral formulas enriched with fish oils are recommended for patients with acute respiratory distress syndrome.
  • Nathan Goodyear on 21 Mar 11
     
    nutrition to improve inflammation in surgical patiens
Nathan Goodyear

Tumor regionalization after surgery: Roles of the tumor microenvironment and neutrophil... - 0 views

www.nature.com/...s12276-022-00784-2

TME NETosis metastasis surgery cancer tumor microenvironment

shared by Nathan Goodyear on 20 Apr 23 - No Cached
  • tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure.
  • NETosis, which is the process of forming neutrophil extracellular traps (NETs)
  • surgery-induced metastasis
  • ...61 more annotations...
  • surgery per se can promote cancer metastasis through a series of local and systemic events
  • surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Key point; add to presentation on surgery and metastasis
  • After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear
  • infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients
  • Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis
  • Surgery-induced cancer metastasis has been well established in animal models
  • tumor cell dissemination, tumor-favoring immune responses, and neoangiogenesis
  • the surgical resection of primary tumors is beneficial is controversial
  • CTCs abruptly increase just after surgery
  • Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer
  • excessive glucocorticoids negatively modulate immune functions
  • immune surveillance against tumors is considered to be impaired by surgical stress
  • In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla
  • NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids
  • In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases
  • primary tumors may secrete angiogenic inhibitors as well as angiogenic activators
  • second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment.
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Another key point
  • double-edged sword
  • HIF-1 in neutrophils plays a critical role in NETosis and bacteria-killing activity
  • neutrophils play various roles in the initiation and progression of cancer
  • NETosis
  • many inflammatory and neoplastic diseases
  • formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins1
  • NETosis has been highlighted as an inflammatory event that promotes cancer metastasis
  • Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves
  • A series of these events is called NETosis.
  • neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins
  • innate immune response against infection
  • Neutrophils are the most abundant type of granulocytes, comprising 40–70% of all white blood cells
  • two types of NEToses, suicidal (or lytic) NETosis and vital NETosis
  • Suicidal NETosis mainly depends on the production of reactive oxygen species (ROS)
  • Since neutrophils die during this process, it is called suicidal NETosis.
  • vital NETosis
  • vital NETosis occurs independently of ROS production
  • Vital NETosis can be induced by Gram-negative bacteria. LPS
  • NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia
  • neutrophils actively undergo NETosis in the tumor microenvironment
  • Hypoxia
  • NETosis plays a pivotal role in noninfectious autoimmune diseases,
  • cytokines
  • tumor-derived proteases
  • tumor exosomes
  • NETosis generally actively progresses in the tumor microenvironment.
  • the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.
  • NETosis is a defense system to protect the body from invading pathogens
  • when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences
  • plasma levels of NETosis markers are elevated after major surgeries
  • local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases
  • NETs promote metastasis at multiple steps
  • NETs loosen the ECM and capillary wall to promote the intravasation of cancer cells
  • NETs and platelets wrap CTCs, which protects them from attack by immune cells and shearing force by blood flow
  • NETs promote the local invasion of cancer cells by degrading the extracellular matrix (ECM)
  • neutrophil elastase, matrix metalloproteinase 9, and cathepsin G
  • NETs also promote the intravasation of cancer cells
  • millions of tumor cells are released into the circulation every day,
  • NETs can wrap up CTCs with platelets
  • β1-integrin plays an important role in the interaction between CTCs and NETs
  • NET-platelet-CTC aggregates.
  • After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow late
  • NETs are believed to participate in the reactivation of dormant cancer cells in metastatic regions
  • NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells
  • Nathan Goodyear on 20 Apr 23
     
    Surgery induced metastasis: it is real and steered by NETosis.
Nathan Goodyear

Frontiers | Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic M... - 0 views

www.frontiersin.org/...full

press-pulse therapy hyperbaric ketogenic metabolic therapy cancer ketogenic diet Glioblastoma glioblastoma multiforme HBOT nutrition

shared by Nathan Goodyear on 01 Apr 18 - No Cached
  • The SOC for GBM was modified in this patient to initiate KMT prior to surgical resection, to eliminate steroid medication, and to include HBOT as part of the therapy
  • the greatest therapeutic benefit for patients (near 1.0)
  • The observed reduction in blood glucose in our patient would reduce lactic acid fermentation in the tumor cells, while the elevation of ketone bodies would fuel normal cells thus protecting them from hypoglycemia and oxidative stress
  • ...30 more annotations...
  • Previous studies showed that GBM survival and tumor growth was correlated with blood glucose levels
  • Evidence indicates that glioma cells cannot effectively use ketone bodies for energy due to defects in the number, structure, and function of their mitochondria
  • The accuracy of the GKI as a predictor for therapeutic efficacy, however, is better when ketone bodies are measured from the blood than when measured from the urine
  • A reduction of glucose-driven lactic acid fermentation would not only increase tumor cell apoptosis, but would also reduce inflammation and edema in the tumor microenvironment thus reducing tumor cell angiogenesis and invasion
  • Besides serving as a metabolic fuel for GBM, glutamine is also an essential metabolite for normal immune cells
  • therapies that inhibit glutamine availability and utilization must be strategically employed to avoid inadvertent impairment of immune cell functions
  • we used the non-toxic green tea extract, EGCG, and chloroquine in an attempt to limit glutamine availability to the tumor cells
  • EGCG is thought to target the glutamate dehydrogenase activity that facilitates glutamine metabolism in GBM cells
  • Chloroquine, on the other hand, will inhibit lysosomal digestion thus restricting fermentable amino acids and carbohydrates from phagocytosed materials in the tumor microenvironment
  • HBOT to increase oxidative stress in the tumor cells
  • As glucose and glutamine fermentation protect tumor cells from oxidative stress, reduced availability of these metabolites under ketosis could enhance the therapeutic action of HBOT, as we recently described
  • Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast
  • Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day
  • KD (increased to 1,500 kcal/day at day 22
  • the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA)
  • Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D
  • This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies
  • Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers
  • less than 20% of younger adults generally survive beyond 24 months
  • glucose and glutamine are the primary fuels that drive the rapid growth of most tumors including GBM
  • Glucose drives tumor growth through aerobic fermentation (Warburg effect), while glutamine drives tumor growth through glutaminolysis
  • The fermentation waste products of these molecules, i.e., lactic acid and succinic acid, respectively, acidify the tumor microenvironment thus contributing further to tumor progression
  • Glucose and glutamine metabolism is also responsible for the high antioxidant capacity of the tumor cells thus making them resistant to chemo- and radiotherapies
  • The reliance on glucose and glutamine for tumor cell malignancy comes largely from the documented defects in the number, structure, and function of mitochondria and mitochondrial-associated membranes
  • These abnormalities cause the neoplastic GBM cells to rely more heavily on substrate level phosphorylation than on oxidative phosphorylation for energy
  • dexamethasone not only increases blood glucose levels but also increases glutamine levels through its induction of glutamine synthetase activity
    • Nathan Goodyear
      Nathan Goodyear on 21 May 18
       
      use mannitol instead
  • Calorie restriction and restricted KD are anti-angiogenic, anti-inflammatory, anti-invasive, and also kill tumor cells through a proapoptotic mechanism
  • Evidence also shows that therapeutic ketosis can act synergistically with several drugs and procedures to enhance cancer management improving both progression free and overall survival
  • hyperbaric oxygen therapy (HBOT) increases oxidative stress on tumor cells especially when used alongside therapies that reduce blood glucose and raise blood ketones
  • The glutamine dehydrogenase inhibitor, epigallocatechin gallate (EGCG) is also proposed to target glutamine metabolism
  • Nathan Goodyear on 01 Apr 18
     
    Case study of Glioblastoma treated with ketogenic metabolic therapy as an adjuct to modified standard therapy.
Nathan Goodyear

Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2... - 0 views

www.nature.com/...s41698-017-0044-8

cancer cancer stem cells liver cancer vitamin C IV vitamin C oncology

shared by Nathan Goodyear on 30 Jan 18 - No Cached
  • Chen et al. have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.
  • Ascorbic acid (the reduced form of vitamin C) is specifically transported into cells by sodium-dependent vitamin C transporters (SVCTs)
  • SVCT-1 is predominantly expressed in epithelial tissues
  • ...41 more annotations...
  • whereas the expression of SVCT-2 is ubiquitous
  • differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.
  • high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.
  • Hepatocellular carcinoma (HCC)
  • The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells
  • DNA double-strand damage was found following VC treatment
  • DNA damage was prevented by NAC
  • Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight
  • Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs
  • VC is one of the numerous common hepatoprotectants.
  • Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells
  • we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.
  • Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients
  • Median DFS time for VC users was 25.2 vs. 18 months for VC non-users
  • intravenous VC use is linked to improved DFS in HCC patients.
  • In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      the authors here made similar mistakes to the Mayo authors i.e. under doses here in this study.  They dosed at only 2 grams IVC.  A woefully low dose of IVC.
  • Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      positive results despite a low dose used.
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      Their comfort zone was 1mM.  They should have targeted 20-40 mM.
  • Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy
  • As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity
  • we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs
  • SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC
  • CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance
  • we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death
  • as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs
  • In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells
  • we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo
  • Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      so, exclude the benefit to patients until the exact mechanism of action, which will never be fully elicited?!?!?
  • Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      Terribly inadequate dose.  Target is 20-40 mM which other studies have found occur with 50-75 grams of IVC.
  • several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS
  • high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo
  • high recurrence rate and heterogeneity
  • tumor progression, metastasis, and chemotherapy-resistance
  • SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues
  • high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior
  • SVCT-2 is enriched in liver CSCs
  • these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.
  • pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration
  • The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner
  • VC and cisplatin combination further caused cell apoptosis in tumor xenograft
  • These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response
  • qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs
  • Nathan Goodyear on 30 Jan 18
     
    IV vitamin C in vitro and in vivo found to "preferentially" eradicate cancer stem cells.  In addition, IV vitamin C was found to be adjunctive to chemotherapy, found to be hepatoprotectant.  This study also looked at SVCT-2, which is the transport protein important in liver C uptake.
wheelchairindia9

PF Night Splint Derotation - 0 views

www.wheelchairindia.com/...PF-Night-Splint-Derotation

Understanding The Role Of Treating Night Splints plantar fascia and intrinsic musculature Derotation foot splinting provides support to the knee multiple orthopedic problems Less slippage of product

shared by wheelchairindia9 on 21 Mar 16 - No Cached
  • wheelchairindia9 on 21 Mar 16
     
    PF Night Splint (Derotation) Applications Prevention and correction of foot drop. Night splint for early healing. Ambulatory, can be used as a day splint. Perfect post-operative immobilisation and derotation. Peroneal / Peritibial nerve or muscle damage. Ankle or Plantar flexion contracture and functional alignment. Can be used to protect the diabetic/ injured ankle & foot. PF Night Splint (Derotation) Features Removable de-rotation bar. Moulded foot casing, aesthetically pleasing and durable. Effective Liner, improved comfort. Highly functional Design, customized degree of dorsiflexion. Double strapping mechanism, better grip.
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