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Nathan Goodyear

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patie... - 0 views

science.sciencemag.org/...595

immunotherapy gut bacteria melanoma cancer PD-1 gut flora gut microbiota gut microbiome

shared by Nathan Goodyear on 07 Feb 21 - No Cached
  • Nathan Goodyear on 07 Feb 21
     
    Fecal transplant study. Gut microbes improve efficacy of anti-PD-1 therapy immunotherapy.
Nathan Goodyear

Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in m... - 0 views

www.ncbi.nlm.nih.gov/...PMC6727487

ctDNA melanoma cancer

shared by Nathan Goodyear on 06 Jul 23 - No Cached
  • Nathan Goodyear on 06 Jul 23
     
    Title tells it all, ctDNA decrease levels portends treatment response.
Nathan Goodyear

Temperature-dependent and time-dependent effects of hyperthermia mediated by dextran-co... - 0 views

www.ncbi.nlm.nih.gov/...PMC4346362

hyperthermia

shared by Nathan Goodyear on 18 Apr 23 - No Cached
  • Nathan Goodyear on 18 Apr 23
     
    effect of time and temperature on the viability of melanoma cell lines and expression of HSP 70 & 90 after brief exposure to hyperthermia. While hyperthermia has multiple mechanisms of action, this paper elucidates two essential benefits of high-dose hyperthermia. First, the study illustrates why high-dose hyperthermia treatments (45°C - 47°C) are so much more effective than the low-dose hyperthermia (39°C - 43°C) produced by commercially available heating devices.
Nathan Goodyear

Effects of Tocopherol (Vitamin E) Acid Succinate on Morphological Alterations and Growt... - 0 views

cancerres.aacrjournals.org/...550.abstract

Vitamin E Tocopherol cancer synthetic natural

shared by Nathan Goodyear on 10 Feb 11 - No Cached
  • Nathan Goodyear on 10 Feb 11
     
    synthetic nutrients less effective against cancer, than natural nutrients
Nathan Goodyear

Avoidance of sun exposure is a risk factor for all-cause mortality: results from the Me... - 0 views

onlinelibrary.wiley.com/...abstract

vitamin D sun exposure mortality

shared by Nathan Goodyear on 16 Nov 14 - No Cached
  • Nathan Goodyear on 16 Nov 14
     
    Swedish Cohort finds low sun exposure is associated with increased mortality.
Nathan Goodyear

Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c p... - 0 views

www.ncbi.nlm.nih.gov/...27457663

Cancer RIGVIR immunotherapy immunotherapy cancer

shared by Nathan Goodyear on 19 Oct 18 - No Cached
  • Nathan Goodyear on 19 Oct 18
     
    3 cases reports of the use of the oncolytic RIGVIR virus in stage III and stage IV disease.
Nathan Goodyear

Melanoma Unknown Primary Brain Metastasis Treatment with ECHO-7 Oncolytic Virus Rigvir:... - 0 views

www.ncbi.nlm.nih.gov/...PMC5834433

Cancer RIGVIR immunotherapy

shared by Nathan Goodyear on 19 Oct 18 - No Cached
  • Nathan Goodyear on 19 Oct 18
     
    Case study of the oncolytic therapy RIGVIR for Brain metastasis.
Nathan Goodyear

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multi... - 0 views

www.ncbi.nlm.nih.gov/...PMC5809128

cancer anal cancer nivolumab immunotherapy

shared by Nathan Goodyear on 13 Jul 18 - No Cached
  • Patients received a median of six doses of nivolumab
  • four of the first 12 patients had partial responses
  • Nine (24% [95% CI 15–33]) of 37 patients achieved a response (seven partial responses and two complete responses
  • ...16 more annotations...
  • no treatment-related deaths
  • the most common adverse events were anaemia (26 [70%]), fatigue (25 [68%]), and rash
  • hypothyroidism
  • hypothyroidism
  • nivolumab-related autoimmune hypothyroidism, which resolved after a short course of corticosteroids
  • No grade 3 or 4 adverse events occurred
  • Nivolumab resulted in objective responses in 24% of patients with metastatic SCCA
  • Historically, doublet chemotherapy with cisplatin and fluorouracil has been the most common treatment for patients with metastatic SCCA
  • our results suggest that immune checkpoint blockade agents might extend overall survival beyond currently available therapies, especially if provided early in the disease treatment course
  • the dose of nivolumab we used differs from the 2016 recommendation of a fixed 240 mg every 2 weeks
  • 25% of patients develop distant metastases
  • most patients with localised SCCA are cured by chemoradiation
  • More than 90% of cases of SCCA are linked to prior infection with human papillomavirus (HPV)
  • Within tumour cells, HPV oncoproteins are immunogenic and can trigger an anti-tumour host immune response by recruitment of tumour-infiltrating lymphocytes
  • Tumour cells express PD-L1 and, on binding its inhibitory receptor PD-1 on the surface of T cells, downregulate T-cell activation and thwart the local anti-tumour immune response
  • Nivolumab is a humanised monoclonal antibody against PD-1 that disrupts this interaction, enabling T-cell cytotoxicity. It has activity as a monotherapy in advanced solid cancers, such as head and neck cancer, melanoma, non-small-cell lung cancer, and renal cell carcinoma
  • Nathan Goodyear on 13 Jul 18
     
    study finds nivolumab helpful in some patients with surgically unresectable or metastatic anal cancer.  The dose used was 3 mg/kg every 2 weeks. 
Nathan Goodyear

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

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

ivermectin cancer WTF Selamectin

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

Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expec... - 0 views

www.nature.com/ja201711

Ivermectin cancer

shared by Nathan Goodyear on 19 Mar 18 - No Cached
  • The avermectins are known to possess pronounced antitumor activity
  • Over the past few years, there have been steadily increasing reports that ivermectin may have varying uses as an anti-cancer agent, as it has been shown to exhibit both anti-cancer and anti-cancer stem cell properties
  • In human ovarian cancer and NF2 tumor cell lines, high-dose ivermectin inactivates protein kinase PAK1 and blocks PAK1-dependent growth
  • ...13 more annotations...
  • PAK1 is essential for the growth of more than 70% of all human cancers, including breast, prostate, pancreatic, colon, gastric, lung, cervical and thyroid cancers, as well as hepatoma, glioma, melanoma, multiple myeloma and for neurofibromatosis tumors
  • Ivermectin suppresses breast cancer by activating cytostatic autophagy, disrupting cellular signaling in the process, probably by reducing PAK1 expression
  • Cancer stem cells are a key factor in cancer cells developing resistance to chemotherapies and these results indicate that a combination of chemotherapy agents plus ivermectin could potentially target and kill cancer stem cells, a paramount goal in overcoming cancer
  • Triple-negative breast cancers, which lack estrogen, progesterone and HER2 receptors, account for 10–20% of breast cancers and are associated with poor prognosis
  • Ivermectin addition led to transcriptional modulation of genes associated with epithelial–mesenchymal transition and maintenance of a cancer stem cell phenotype in triple-negative breast cancers cells, resulting in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo
  • Ivermectin-induced cytostatic autophagy also leads to suppression of tumor growth in breast cancer xenografts, causing researchers to believe there is scope for using ivermectin to inhibit breast cancer cell proliferation and that the drug is a potential treatment for breast cancer
  • ivermectin synergizes with the chemotherapy agents cytarabine and daunorubicin to induce cell death in leukemia cells
  • Ivermectin inhibits proliferation and increases apoptosis of various human cancers
  • Activation of WNT-TCF signaling is implicated in multiple diseases, including cancers of the lungs and intestine,
  • A new screening system has found that ivermectin inhibits the expression of WNT-TCF targets
  • It represses the levels of C-terminal β-catenin phosphoforms and of cyclin D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases
  • In vivo, ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without side effects
  • ivermectin has an exemplary safety record, it could swiftly become a useful tool as a WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases, encompassing multiple cancers.117
  • Nathan Goodyear on 19 Mar 18
     
    Ivermectin shows promise and usefullness in several cancer types.  This is a review article.
Nathan Goodyear

IL-2: The First Effective Immunotherapy for Human Cancer | The Journal of Immunology - 0 views

www.jimmunol.org/...5451

cancer IL-2 Treg immune system immunology

shared by Nathan Goodyear on 17 Apr 18 - No Cached
  • IL-2 is a 15.5-kDa cytokine secreted predominately by Ag-simulated CD4+ T cells, but it can also be produced by CD8+ cells, NK cells, and activated dendritic cells
  • IL-2 is the predominant factor responsible for the maintenance of CD4+ regulatory T cells
  • A generalized capillary leak syndrome was induced by IL-2 in vivo that resulted in interstitial pulmonary infiltrates and substantial weight gain in patients
  • ...4 more annotations...
  • The side effects were transient and returned to baseline following treatment
  • Tumors do not express IL-2 receptors and thus the antitumor activity was the result of IL-2 stimulation of immune cell
  • Patients with metastatic melanoma or metastatic renal cell cancer were uniquely responsive to high-dose IL-2 administration, and except for patients with advanced non-Hodgkin’s lymphomas (35) only rare responses were seen in patients with other tumor types
  • The underlying toxicity of IL-2 results from a capillary leak that leads to fluid extravasation into visceral organs that can compromise their function
  • Nathan Goodyear on 17 Apr 18
     
    Great review of the history of IL-2 in the treatment of cancer.  IL-2 stimulates the immune system to attack cancer.  Don't reinvent the wheel; use what is already present and available.
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