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Nathan Goodyear

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer | Proceedings of the National Academy of Sciences - 0 views

www.pnas.org/E7301

Ivermectin cancer ovarian cancer oncogene oncogenes

shared by Nathan Goodyear on 20 Mar 18 - No Cached
  • we functionally validated a potent EOC oncogene, KPNB1, and showed its clinical relevance to human EOC
  • a well-established antiparasitic drug, ivermectin, has antitumor effects on EOC through its inhibition of KPNB1
  • EOC has high intertumor and intratumor heterogeneity at the molecular and epigenetic levels
  • ...22 more annotations...
  • the mortality rate of EOC has not been significantly changed for several decades
  • Sequencing revealed that almost all tumors (96%) had mutations in TP53, which serves as a major driver of this cancer
  • Low-prevalence but statistically significant mutations in nine other genes including NF1, BRCA1, BRCA2, RB1, and CDK12 were also identified, but the majority of genes were mutated at low frequency, making it difficult to distinguish between driver and passenger mutations
  • KPNB1 inhibition via any of three KPNB1 siRNAs or importazole treatment induced apoptosis in human EOC cell lines (Fig. 3 A–F and Fig. S4), and was accompanied by an increase in the expression levels of the proapoptotic proteins BAX and cleaved caspase-3
  • Stable overexpression of KPNB1 in SKOV3 and OVCAR3 (Fig. S6) significantly accelerated cell proliferation/survival (Fig. 5 A–C), confirming that KPNB1 functions as an oncogene in EOC
  • KPNB1 overexpression significantly decreased caspase-3/7 activity (Fig. 5D), in addition to the expression levels of cleaved caspase-3 and BAX proteins (Fig. 5E). KPNB1 overexpression also decreased p21 and p27 protein levels (Fig. 5E), as opposed to their increase by KPNB1 inhibition
  • KPNB1 functions as an antiapoptotic and proproliferative oncogene in EOC.
  • Patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1
  • KPNB1 acts as an oncogene in human EOC and represents a promising therapeutic target.
  • ivermectin treatment suppressed cell proliferation/viability in a dose-dependent manner (Fig. 7A), indicating that it exerts an antitumor effect on EOC
  • ivermectin also induced apoptosis
  • ivermectin increased the expression levels of BAX, and cleaved PARP, as well as p21 and p27
  • KPNB1 inhibition is responsible for the antitumor effect of ivermectin
  • we found that ivermectin synergistically reduced cell proliferation/viability in combination with paclitaxel in human EOC cells
  • Single treatment of ivermectin or paclitaxel reduced tumor growth in nude mice, but, notably, combination treatment of ivermectin and paclitaxel almost completely suppressed tumor growth
  • ERBB2, is amplified and overexpressed in many cancers, including breast (31), ovary (31), colon (32), bladder (33), non-small-cell lung (34), and gastric cancer (35), and is a poor prognostic factor in certain cancer types
  • KPNB1 was the second-highest-ranked gene identified in our screen
  • Increased KPNB1 protein levels have been reported in several cancers, including cervical cancer (42), hepatocellular carcinoma (43), and glioma (44), suggesting KPNB1’s oncogenic potential in these tumor types
  • our findings suggest that KPNB1 might serve as a master regulator of cell cycle by regulating several cell cycle-related proteins, including p21, p27, and APC/C family members
  • higher and/or more-frequent doses of ivermectin than currently approved for humans are well tolerated in humans
  • none of the mice in this study treated with the effective dosage of ivermectin for in vivo anticancer therapy showed severe adverse event
  • we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC cell lines than either drug alone
  • Nathan Goodyear on 20 Mar 18
     
    Ivermectin found to be pro-apoptotic for the epithelial ovarian cancer oncogene, KPNB1 in in Vivo study.  This effective anti-parasitic drug inhibits the KPNB1 oncogene.
Nathan Goodyear

microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Comparative Analysis | Scientific Reports - 0 views

www.nature.com/...s41598-017-16978-y

genetics cancer epigenetics breast cancer

shared by Nathan Goodyear on 06 Feb 18 - No Cached
mamdouh_hfz liked it
  • dysregulated miRNA could be involved in tumor cell proliferation and growth as well as cell cycle progression
  • under-expression of miR-497, 376c and 1271 in Lebanese breast cancer tissues
  • The upregulated miR-183 in our samples was predicted to be responsible for the decrease in expression of the BTG1 mRNA whose protein is involved in cell cycle arrest and apoptosis in breast cancer cells18.
  • ...9 more annotations...
  • nother molecule related to cell proliferation that was over-expressed in our data and suggested as a target of downregulated miR-376c is AURKA
  • the over-expression of miR-183 and miR-21 in Lebanese breast cancer tissues is consistent with downregulation of two important tumor suppressor predicted targets: AKAP12 whose protein regulates cellular adhesion dynamics by controlling cytoskeletal architecture, cell migration, and mitogenic signaling20; and LATS2 whose protein causes cell cycle arrest
  • dysregulation in cancer particularly in breast cancer highlights their importance in tumor development
  • mRNA-miRNA integration analysis of early breast cancer revealed a potential role of miRNA in increasing cellular proliferation and progression, and decreasing invasion and migration
  • most of the miRNA dysregulated in Lebanese breast cancer patients are similar to those dysregulated in American patients, differences in miRNA expression exist and could be attributed either to the patients’ age at diagnosis or to ethnic variation in miRNA epigenetic regulation and sequence variation of pre-miRNA
  • the number one cancer killer of women worldwide
  • microRNA (miRNA) are small non-coding 18–25 nucleotide RNA molecules currently being studied as potential diagnostic, prognostic and therapeutic biomarkers for cancer and other diseases
  • Extensive research on these post-transcriptional modulators has proven that they are deregulated in breast cancerous tissues and even in biological fluids from breast cancer patients
  • five candidate miRNAs (miR-10b, miR-148b, miR-221, miR-21, and miR-155)
  • Nathan Goodyear on 06 Feb 18
     
    Epigenetics plays a role, via disregulated miRNA, in increased cell growth, progression, and invasion in Lebanese women with breast cancer.  It is not just genetics that play a role, but epigenetics.
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

Cancers | Free Full-Text | A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers | HTML - 0 views

www.mdpi.com/htm

cancer Niclosamide ivermectin Wnt

shared by Nathan Goodyear on 16 Apr 18 - No Cached
  • To date nearly half of known human tumors show a dysregulation of the WNT signaling pathway
  • It should be also noted that the WNT pathway is not exclusively employed during development or overactivated in cancer. In adults many healthy tissues rely on it for renewal and homeostasis maintenance, most notably the intestine, haematopoietic system, hair, bones and skin. Therefore one might expect adverse reactions in all these organ systems, which has indeed been observed for many WNT-targeting compounds upon attempts to push them into the clinics
  • The intestine seems to be the most vulnerable in this regard
  • ...8 more annotations...
  • Ivermectin inhibits proliferation of human colon cancer and lung cancer cells both in vitro and in vivo
  • The anti-proliferative action, affecting both the bulk tumor cells and CSCs, was linked in this study to inhibition of WNT signaling
  • the anti-WNT IC50 of ivermectin is 5–10 times (~1–2 µM vs. 10 µM) lower than that of its toxic effect against chloride channels
  • oral bioavailability of the drug, as for other antiparasitic drugs discussed in this section, is very low
  • Toxicity studies in vivo have also demonstrated a wide therapeutic index for ivermectin
  • Its anti-proliferative activity has been demonstrated in a wide array of cancer cell lines representative of WNT-dependent cancers: non-small lung carcinoma [96], multiple myeloma [97], hepatoma [98], adrenocortical carcinoma [99], ovarian cancer [100] and glioblastoma
  • Niclosamide inhibits the canonical WNT pathway
  • In addition to inhibiting the canonical WNT pathway, niclosamide may mediate its anticancer activities through several other signaling pathways such as NOTCH [107], MTOR [108], NF-κB [97] and STAT3 [96]
  • Nathan Goodyear on 16 Apr 18
     
    review article highlights older medications that have anti-Wnt pathway effects in cancer.  Roughly, 50% of cancer involve upregulated Wnt pathway activity. Other drugs of note: metformin
Nathan Goodyear

The combination of artesunate and carboplatin exerts a synergistic anti-tumour effect on non-small cell lung cancer. - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...32072678

cancer chemotherapy artesunate lung cancer

shared by Nathan Goodyear on 12 Apr 20 - No Cached
  • Nathan Goodyear on 12 Apr 20
     
    Artesunate and carboplatin chemotherapy shows synergistic anti-cancer effects.
Nathan Goodyear

PD-L1 Expression in Circulating Tumor Cells Increases during Radio(chemo)therapy and Indicates Poor Prognosis in Non-small Cell Lung Cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC6345864

CTC radiation circulating tumor cells

shared by Nathan Goodyear on 13 Apr 20 - No Cached
  • Nathan Goodyear on 13 Apr 20
     
    Radiation increases CTC and PD-L1 expression on the CTC.
Nathan Goodyear

Frontiers | Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer's Disease Brain | Immunology - 0 views

journal.frontiersin.org/...full

LPS lipopolysaccharides Alzheimer's disease brain inflammation

shared by Nathan Goodyear on 23 Sep 17 - No Cached
  • lipopolysaccharides (LPS), either alone or in combination, have indicated that when compared, bacterial LPSs exhibit the strongest induction of pro-inflammatory signaling in human neuronal–glial cells in primary coculture of any single inducer, and different LPS extracts from different gastrointestinal (GI)-tract resident Gram-negative bacteria appeared to have different pro-inflammatory potential
  • powerful inducer of the NF-κB
  • In both neocortex and hippocampus, LPS has been detected to range from a ~7- to ~21-fold increase abundance in AD brain
  • ...15 more annotations...
  • Major Gram-negative bacilli of the human GI-tract, such as the abundant B. fragilis and Escherichia coli (E. coli), are capable of discharging a remarkably complex assortment of pro-inflammatory neurotoxins
  • (i) bacterial amyloids (10, 21); (ii) endotoxins and exotoxins (5, 12); (iii) LPS (12, 18); and (iv) small non-coding RNAs (sncRNAs)
  • integral components of the outer leaflet of the outer membrane of Gram-negative bacteria, LPS
  • LPS, the major molecular component of the outer membrane of Gram-negative bacteria normally serves as a physical barrier providing the bacteria protection from its surroundings
  • LPS is also recognized by the immune system as a marker for the detection of bacterial pathogen invasion and responsible for the development of inflammatory response is perhaps the most potent stimulator and trigger of inflammation known
  • AD-affected brains have remarkably large loads of bacterial-derived toxins compared to controls. The transfer of noxious, pro-inflammatory molecules from the GI-tract microbiome to the CNS may be increasingly important during the course of aging when both the GI-tract and blood–brain barriers become significantly more permeable
  • first evidence of a perinuclear association of LPS with AD brain cell nuclei
  • LPS-mediated stimulation of chronic inflammation, beta-amyloid accumulation, and episodic memory decline in murine models of AD (39, 40) and a biophysical association of LPS with amyloid deposits and blood vessels in human AD patients
  • Strong adherence of LPS to the nuclear periphery has recently been shown to inhibit nuclear maturation and function that may impair or block export of mRNA signals from brain cell nuclei, a highly active organelle with extremely high rates of transcription, mRNA processing, and export into the cytoplasm
  • LPS may be further injurious to the nuclear membrane just as LPS contributes to cerebrovascular endothelial cell membrane injury
  • high intake of dietary fiber is a strong inhibitor of B. fragilis abundance and proliferation in the intact human GI-tract and as such is a potent inhibitor of the neurotoxic B. fragilis-derived amyloids, LPS, enterotoxins, and sncRNAs.
  • GI-tract microbiome-derived LPS may be an important initiator and/or significant contributor to inflammatory degeneration in the AD CNS
  • LPS has been recently localized to the same anatomical regions involved in AD-type neuropathology
  • a known pro-inflammatory transcription factor complex that triggers the expression of pathogenic pathways involved in neurodegenerative inflammation
  • pro-inflammatory amyloids, endo- and exotoxins, LPSs, and sncRNAs but also serve as potent sources of membrane-disrupting agents
  • Nathan Goodyear on 23 Sep 17
     
    LPS links gut to inflammation in Alzheimer's disease
Nathan Goodyear

Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Post-Treatment in Rhesus Macaques - The American Journal of Pathology - 0 views

ajp.amjpathol.org/...fulltext

Lyme Lyme disease borrelia burgdorferi

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

The prognostic impact of traditional Chinese medicine monomers on tumor-associated macrophages in non-small cell lung cancer - PubMed - 0 views

pubmed.ncbi.nlm.nih.gov/31703753

TCM Traditional Chinese Medicine cancer resveratrol curcumin

shared by Nathan Goodyear on 04 May 21 - No Cached
  • Nathan Goodyear on 04 May 21
     
    Brief review of proposed mechanisms of TCM actions with TAMs in the TME in various cancers.
Nathan Goodyear

Quercetin suppresses the metastatic ability of lung cancer through inhibiting Snail-dependent Akt activation and Snail-independent ADAM9 expression pathways - PubMed - 0 views

pubmed.ncbi.nlm.nih.gov/28648644

Snail quercetin non-small cell lung cancer lung cancer Akt

shared by Nathan Goodyear on 20 May 21 - No Cached
  • Nathan Goodyear on 20 May 21
     
    Quercetin effective in inhibiting EMT and Akt proliferation signaling.
Nathan Goodyear

Quercetin Inhibits the Proliferation and Metastasis of Human Non-Small Cell Lung Cancer Cell Line: The Key Role of Src-Mediated Fibroblast Growth Factor-Inducible 14 (Fn14)/Nuclear Factor kappa B (NF-κB) pathway - 0 views

www.ncbi.nlm.nih.gov/...PMC7144538

Src Quercetin cancer NF-kappaB

shared by Nathan Goodyear on 20 May 21 - No Cached
  • Nathan Goodyear on 20 May 21
     
    Quercetin inhibits NF-kappaB through src suppression.
Nathan Goodyear

Mistletoe (Viscum album) extract targets Axl to suppress cell proliferation and overcome cisplatin- and erlotinib-resistance in non-small cell lung cancer cells - 0 views

www.sciencedirect.com/...S0944711317301356

cancer mistletoe

shared by Nathan Goodyear on 01 Jun 19 - No Cached
  • Nathan Goodyear on 01 Jun 19
     
    Mistletoe found to inhibit cancer cell proliferation and reduce chemo-resistance.
Nathan Goodyear

Tumor-associated inflammatory microenvironment in non-small cell lung cancer: correlation with FGFR1 and TLR4 expression via PI3K/Akt pathway - 0 views

www.ncbi.nlm.nih.gov/...PMC6400805

cancer TLR-4 TLR4

shared by Nathan Goodyear on 16 Jun 20 - No Cached
  • Nathan Goodyear on 16 Jun 20
     
    TLR-4 receptor implicated in Akt/PI3k/mTOR pathway stimulation/activation in cancer.
Nathan Goodyear

Dihydroartemisinin and artesunate inhibit aerobic glycolysis via suppressing c-Myc signaling in non-small cell lung cancer - PubMed - 0 views

pubmed.ncbi.nlm.nih.gov/35149053

artesunate cancer c-myc

shared by Nathan Goodyear on 21 Sep 22 - No Cached
  • Nathan Goodyear on 21 Sep 22
     
    Artesunate inhibits c-myc
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