The words people choose to use hold a lot of power, whether that be in spreading truth or deception. As listeners and readers, we do our best to understand how words are being used. There are many ...current methods in computer science literature attempting to embed words into numerical information for statistical analyses. Some of these embedding methods, such as Bag of Words, treat words as independent, while others, such as Word2Vec, attempt to gain information about the context of words. It is of interest to compare how well these various methods of translating text into numerical data work specifically with detecting fake news. The term “fake news” can be quite divisive, but we define it as news that is hyper-partisan, filled with untruths, and written to cause anger and outrage, as defined in Potthast & Kiesel (2018). We hypothesize a person’s word choice relates to the factualness of an article. In Chapter 5, we utilize this embedded information in several binary classification methods. We find that words are only marginally valuable in detecting fake news regardless of the embedding or classification method used. However, within natural language processing tasks, there are many preprocessing steps taken to get the text ready for analysis, which is explored in Chapter 6. The embedding methods are confounded with the preprocessing methods used. Preprocessing of text includes, but is not limited to, filtering out words that do not appear a minimum number of times, filtering out stop words, removing numbers, and translating all letters to lower case. We find filtering out stop words and removing words not appearing a minimum number of times have the most significant effect in combination with embedding and classification methods. Finally, in Chapter 7, we extend the classification to six categories ranging from true to pants-on-fire false and found these preprocessing methods are not as influential as they were with the binary outcome. Other predictors outside of the words and word embeddings themselves are necessary for improvement in the detection of fake news.
Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), treatment is inevitably hampered by the development of drug resistance. Thus, new drugs are ...urgently needed. We investigated the efficacy, toxicity, and mechanism of action of the marine triterpene glycoside cucumarioside Asub.2 -2 (CAsub.2 -2) using an in vitro CRPC model. CAsub.2 -2 induced a Gsub.2 /M-phase cell cycle arrest in human prostate cancer PC-3 cells and caspase-dependent apoptosis executed via an intrinsic pathway. Additionally, the drug inhibited the formation and growth of CRPC cell colonies at low micromolar concentrations. A global proteome analysis performed using the 2D-PAGE technique, followed by MALDI-MS and bioinformatical evaluation, revealed alterations in the proteins involved in cellular processes such as metastatic potential, invasion, and apoptosis. Among others, the regulation of keratin 81, CrkII, IL-1β, and cathepsin B could be identified by our proteomics approach. The effects were validated on the protein level by a 2D Western blotting analysis. Our results demonstrate the promising anticancer activity of CAsub.2 -2 in a prostate cancer model and provide insights on the underlying mode of action.
Despite recent advances in the treatment of metastatic castration‐resistant prostate cancer (CRPC), outcome of patients remains poor due to the development of drug resistance. Thus, new drugs are ...urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. FrA revealed high efficacy in human prostate cancer cells, while non‐malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR‐V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase‐dependent or ‐independent apoptosis. Up‐regulation or induction of several pro‐apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase‐3 and down‐regulation of anti‐apoptotic proteins (survivin and Bcl‐2) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL‐1β and cathepsin B. Inhibition of pro‐survival autophagy was observed following FrA exposure. In vivo, FrA inhibited tumor growth of PC‐3 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune modulating effect of FrA. In conclusion, our results suggest that FrA is a promising new drug for the treatment of mCRPC. Induction of apoptosis, inhibition of pro‐survival autophagy, and immune modulatory effects are suspected modes of actions.
What's new?
Prognosis of patients with metastatic castration‐resistant prostate cancer (CRPC) remains poor due to the development of drug resistance. Here, the authors investigated the efficacy, toxicity and mechanism of action of the novel marine compound triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. They found that FrA inhibits human prostate cancer cells, including those resistant to docetaxel, abiraterone and enzalutamide. Remarkably, FrA simultaneously induces apoptosis and cell cycle arrest and suppresses pro‐survival autophagy. FrA also decreases local tumor growth and metastatic spread in vivo without significant toxicities, with immune‐modulating effects potentially contributing to the activity.
Five new β-resorcylic acid derivatives, 14-hydroxyasperentin B (1), β-resoantarctines A-C (3, 5, 6) and 8-dehydro-β-resoantarctine A (4), together with known 14-hydroxyasperentin ...(5′-hydroxyasperentin) (2), were isolated from the ethyl acetate extract of the fungus Penicillium antarcticum KMM 4685 associated with the brown alga Sargassum miyabei. The structures of the compounds were elucidated by spectroscopic analyses and modified Mosher’s method, and the biogenetic pathways for compounds 3–6 were proposed. For the very first time, the relative configuration of the C-14 center of a known compound 2 was assigned via analyses of magnitudes of the vicinal coupling constants. The new metabolites 3–6 were biogenically related to resorcylic acid lactones (RALs); however, they did not possess lactonized macrolide elements in their structures. Compounds 3, 4 and 5 exhibited moderate cytotoxic activity in LNCaP, DU145 and 22Rv1 human prostate cancer cells. Moreover, these metabolites could inhibit the activity of p-glycoprotein at their noncytotoxic concentrations and consequently synergize with docetaxel in p-glycoprotein-overexpressing drug-resistant cancer cells.
Advanced urothelial carcinomas represent a considerable clinical challenge as they are difficult to treat. Platinum-based combination regimens obtain response rates ranging from 40 to 70% in ...first-line therapy of advanced urothelial carcinoma. In the majority of cases, however, the duration of these responses is limited, and when progression occurs, the outcome is generally poor. Therefore, novel therapeutic strategies are urgently needed. The purpose of the current research is to investigate the anticancer effects and the mode of action of the marine triterpene glycoside frondoside A in p53-wild type and p53-deficient human urothelial carcinoma cells.
Activity of frondoside A was examined in the human urothelial carcinoma cell lines RT112, RT4, HT-1197, TCC-SUP, T-24, and 486p. Effects of frondoside A on cell viability, either alone or in combination with standard cytotoxic agents were investigated, and synergistic effects were analyzed. Pro-apoptotic activity was assessed by Western blotting and FACS, alone and in combination with a caspases-inhibitor. The impact of functional p53 was investigated by siRNA gene silencing and the p53 inhibitor pifithrin-α. Effects on autophagy were studied using LC3B-I/II and SQSTM/p62 as markers. The unpaired Student's t-test was used for comparison of the data sets.
Frondoside A shows high cytotoxicity in urothelial carcinoma cells with IC
ranging from 0.55 to 2.33 μM while higher concentrations of cisplatin are required for comparable effects (IC
= 2.03 ~ 5.88 μM). Induction of apoptosis by frondoside A was associated with the regulation of several pro-apoptotic factors, like caspase-3, -8, and -9, PARP, Bax, p21, DNA fragmentation, and externalization of phosphatidylserine. Remarkably, inhibition of p53 by gene silencing or pifithrin-α pretreatment, as well as caspase inhibition, did not suppress apoptotic activity of frondoside A, while cisplatin activity, in contrast, was significantly decreased. Frondoside A inhibited pro-survival autophagy, a known mechanism of drug resistance in urothelial carcinoma and showed synergistic activity with cisplatin and gemcitabine.
A unique combination of properties makes marine compound frondoside A a promising candidate for the treatment of human urothelial carcinomas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Two new guanidine alkaloids, batzelladines O (1) and P (2), were isolated from the deep-water marine sponge Monanchora pulchra. The structures of these metabolites were determined by NMR ...spectroscopy, mass spectrometry, and ECD. The isolated compounds exhibited cytotoxic activity in human prostate cancer cells PC3, PC3-DR, and 22Rv1 at low micromolar concentrations and inhibited colony formation and survival of the cancer cells. Batzelladines O (1) and P (2) induced apoptosis, which was detected by Western blotting as caspase-3 and PARP cleavage. Additionally, induction of pro-survival autophagy indicated as upregulation of LC3B-II and suppression of mTOR was observed in the treated cells. In line with this, the combination with autophagy inhibitor 3-methyladenine synergistically increased the cytotoxic activity of batzelladines O (1) and P (2). Both compounds were equally active in docetaxel-sensitive and docetaxel-resistant prostate cancer cells, despite exhibiting a slight p-glycoprotein substrate-like activity. In combination with docetaxel, an additive effect was observed. In conclusion, the isolated new guanidine alkaloids are promising drug candidates for the treatment of taxane-resistant prostate cancer.
New meroterpenoids, meroantarctines A–C (1–3), with unique 6/5/6/6, 6/5/6/5/6, and 6/5/6/5 polycyclic systems were isolated from the alga-derived fungus Penicillium antarcticum KMM 4685. Their ...structures were elucidated by spectroscopic methods, X-ray diffraction, and quantum chemical calculations. A biogenetic pathway for 1–3 was proposed. Meroantarctines A–C (1–3) inhibited p-glycoprotein activity and could resensitize drug-resistant cancer cells to docetaxel.
Monanchoxymycalin C (MomC) is a new marine pentacyclic guanidine alkaloid, recently isolated from marine sponge Monanchora pulchra by us. Here, anticancer activity and mechanism of action was ...investigated for the first time using a human prostate cancer (PCa) model. MomC was active in all PCa cell lines at low micromolar concentrations and induced an unusual caspase-independent, non-apoptotic cell death. Kinase activity screening identified activation of mitogen-activated protein kinase (MAPK) c-Jun N-terminal protein kinase (JNK1/2) to be one of the primary molecular mechanism of MomC anticancer activity. Functional assays demonstrated a specific and selective JNK1/2 activation prior to the induction of other cell death related processes. Inhibition of JNK1/2 by pretreatment with the JNK-inhibitor SP600125 antagonized cytotoxic activity of the marine compound. MomC caused an upregulation of cytotoxic ROS. However, in contrast to other ROS-inducing agents, co-treatment with PARP-inhibitor olaparib revealed antagonistic effects indicating an active PARP to be necessary for MomC activity. Interestingly, although no direct regulation of p38 and ERK1/2 were detected, active p38 kinase was required for MomC efficacy, while the inhibition of ERK1/2 increased its cytotoxicity. In conclusion, MomC shows promising activity against PCa, which is exerted via JNK1/2 activation and non-apoptotic cell death.
New bicyclic guanidine alkaloid, urupocidin C (Ur-C) along with the previously known urupocidin A (Ur-A) were isolated from the rare deep-sea marine sponge Monanchora pulchra, harvested in ...Northwestern Pacific waters. The unique structure of Ur-C was elucidated using 1D and 2D NMR spectroscopy as well as mass spectra. We discovered a promising selectivity of both alkaloids for human prostate cancer (PCa) cells, including highly drug-resistant lines, compared to non-malignant cells. In cancer cells, marine derived compounds were able to induce G1- and S-cell cycle arrest as well as caspase-mediated cell death. For the first time we have identified mitochondrial targeting as a central mechanism of anticancer action for these and similar molecules. Thus, treatment with the isolated alkaloids resulted in mitochondrial membrane permeabilization consequently leading to the release of cytotoxic mitochondrial proteins to cellular cytoplasm, ROS upregulation, consequent activation of caspase-9 and -3, followed by PARP cleavage, DNA fragmentation, and apoptosis. Moreover, synergistic effects were observed when Ur-A and Ur-C were combined with clinically approved PARP inhibitor olaparib. Finally, these alkaloids exhibited additive effects in combination with docetaxel and androgen receptor inhibitor enzalutamide, both applied in PCa therapy. In conclusion, urupocidin-like compounds are promising lead molecules for the development of new drugs for the treatment of advanced PCa.
Rhizochalinin (Rhiz) is a recently discovered cytotoxic sphingolipid synthesized from the marine natural compound rhizochalin. Previously, Rhiz demonstrated high in vitro and in vivo efficacy in ...various cancer models. Here, we report Rhiz to be highly active in human glioblastoma cell lines as well as in patient-derived glioma-stem like neurosphere models. Rhiz counteracted glioblastoma cell proliferation by inducing apoptosis, G2/M-phase cell cycle arrest, and inhibition of autophagy. Proteomic profiling followed by bioinformatic analysis suggested suppression of the Akt pathway as one of the major biological effects of Rhiz. Suppression of Akt as well as IGF-1R and MEK1/2 kinase was confirmed in Rhiz-treated GBM cells. In addition, Rhiz pretreatment resulted in a more pronounced inhibitory effect of γ-irradiation on the growth of patient-derived glioma-spheres, an effect to which the Akt inhibition may also contribute decisively. In contrast, EGFR upregulation, observed in all GBM neurospheres under Rhiz treatment, was postulated to be a possible sign of incipient resistance. In line with this, combinational therapy with EGFR-targeted tyrosine kinase inhibitors synergistically increased the efficacy of Rhiz resulting in dramatic inhibition of GBM cell viability as well as a significant reduction of neurosphere size in the case of combination with lapatinib. Preliminary in vitro data generated using a parallel artificial membrane permeability (PAMPA) assay suggested that Rhiz cannot cross the blood brain barrier and therefore alternative drug delivery methods should be used in the further in vivo studies. In conclusion, Rhiz is a promising new candidate for the treatment of human glioblastoma, which should be further developed in combination with EGFR inhibitors.
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