IVM can inhibit the replication of flavivirus by targeting the NS3 helicase [17]; it also blocks the nuclear transport of viral proteins by acting on /-mediated nuclear transport and exerts antiviral activity against the HIV-1 and dengue viruses [18]. ). In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [[2], [3], [4], [5]] (Fig. Where are the tablets available without prescription? Further studies showed that IVM could inhibit CSCs by regulating the PAK1-STAT3 axis [96]. Ivermectin, a potential anticancer drug derived from an antiparasitic drug. This study to examine ivermectin, as well as a few other current medications to gauge their effectiveness against COVID-19, goes by the name of ACTIV-6. Moreover, the expression of the homeobox protein NANOG, octamer-binding protein 4 (OCT-4) and SRY-box 2 (SOX-2), which are closely related to the self-renewal and differentiation ability of stem cells in CSCs, were also significantly inhibited by IVM. aAnhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui Province 233030, China, bClinical Medical Department, Bengbu Medical College, Bengbu, Anhui Province 233030, China, cDepartment of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui Province 233030, China, dDepartment of Microbiology and Parasitology, Bengbu Medical College, Bengbu, Anhui Province 233030, China, eSchool of Fundamental Sciences, Bengbu Medical College, Bengbu, Anhui Province 233030, China. (1) Although a large number of research results indicate that IVM affects multiple signaling pathways in tumor cells and inhibits proliferation, IVM may cause antitumor activity in tumor cells through specific targets. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. Top medical journals have rejected a paper about the study, and its main author, Flavio Cadegiani, an endocrinologist at the biotech company Applied Biology, has previously touted unproven COVID-19 medications, such as ivermectin, azithromycin, and antiworm compounds. In animals, it is used as a deworming . Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment. Gao A., Wang X., Xiang W., Liang H., Gao J., Yan Y. Kane N.S., Hirschberg B., Qian S., Hunt D., Thomas B., Brochu R., Ludmerer S.W., Zheng Y., Smith M., Arena J.P., Cohen C.J., Schmatz D., Warmke J., Cully D.F. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. The authors speculated that IVM may mediate the occurrence of pyroptosis via the P2 4/P2 7/NLRP3 pathway (Fig. In a study that screened Wnt pathway inhibitors, IVM inhibited the proliferation of multiple cancers, including the colorectal cancer cell lines CC14, CC36, DLD1, and Ls174 T, and promoted apoptosis by blocking the Wnt pathway [41]. After IVM intervention in breast cancer, the expression of PAK1 was also significantly inhibited, and the use of siRNA to downregulate the expression of PAK1 in tumor cells significantly reduced the anticancer activity of IVM. We believe that IVM can be further developed and introduced clinically as part of new cancer treatments in the near future. IVM has also shown beneficial effects against other parasitic diseases, such as malaria [11,12], trypanosomiasis [13], schistosomiasis [14], trichinosis [15] and leishmaniasis [16]. IVM activates glutamate-gated chloride channels in the parasite, causing a large amount of chloride ion influx and neuronal hyperpolarization, thereby leading to the release of gamma-aminobutyric acid (GABA) to destroy nerves, and the nerve transmission of muscle cells induces the paralysis of somatic muscles to kill parasites [9,10]. EOC is the fifth leading cause of cancer-related deaths in women and has a particularly grim outlook upon diagnosis. p21-activated kinases in cancer. . Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. The DDX23 helicase activity affects the expression of miR-12 [66]. Current Advances in the Treatment of BRAF-Mutant Melanoma. In a study by Hashimoto, it found that IVM inhibited the proliferation of various ovarian cancer cell lines, and the mechanism was related to the inhibition of PAK1 kinase [58]. Diana A., Carlino F., Franzese E., Oikonomidou O., Criscitiello C., De Vita F., Ciardiello F., Orditura M. Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes. . However, the exact molecular target of IVM that affects the Wnt/-catenin pathway remains to be explored. EverythingIsFine . In a previous article titled How Ivermectin Is Useful for Treating Cancer we covered the evidence for the benefits of Ivermectin for cancer. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43]. The functionality is limited to basic scrolling. Identifying the predominant or most important contributor to cell death in each cancer type and environment will be crucial in determining the effectiveness of IVM-based treatments. In addition, morphological changed caused by apoptosis, including chromatin condensation, nuclear fragmentation, DNA fragmentation and apoptotic body formation were observed. 1,553. Intuyod's experiment found that IVM inhibited the proliferation of KKU214 cholangiocarcinoma cells in a dose- and time-dependent manner [44]. Targeted treatment of key mutated genes in cancer, such as EGFR in lung cancer and HER2 in breast cancer, can achieve powerful clinical effects [105,106]. Nappi L., Aguda A.H., Nakouzi N.A., Lelj-Garolla B., Beraldi E., Lallous N., Thi M., Moore S., Fazli L., Battsogt D., Stief S., Ban F., Nguyen N.T., Saxena N., Dueva E., Zhang F., Yamazaki T., Zoubeidi A., Cherkasov A., Brayer G.D., Gleave M. Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Nappi's experiment also proved that IVM combined with erlotinib to achieved a synergistic killing effect by regulating EGFR activity and in HCC827 lung cancer cells [50]. In recent years, many studies have shown that autophagy is a double-edged sword in tumor development. Dominguez-Gomez G., Chavez-Blanco A., Medina-Franco J.L., Saldivar-Gonzalez F., Flores-Torrontegui Y., Juarez M., Diaz-Chavez J., Gonzalez-Fierro A., Duenas-Gonzalez A. Ivermectin as an inhibitor of cancer stemlike cells. IVM selectively inhibits the proliferation of tumors at a dose that is not toxic to normal cells and can reverse the MDR of tumors. Dong Z., Yu C., Rezhiya K., Gulijiahan A., Wang X. Downregulation of miR-146a promotes tumorigenesis of cervical cancer stem cells via VEGF/CDC42/PAK1 signaling pathway. Gewirtz D.A. Drug repositioning is a shortcut to accelerate the development of anticancer drugs. A study published in this week's Journal of the American Medical Association ( JAMA) reported on a double-blind placebo controlled randomized trial of nearly 1600 adults with mild to moderate . Abstract. The FDA-approved drug . Although there is currently little evidences showing that IVM induces pyroptosis, it is important to investigate the role of IVM in inducing pyroptosis in other cancers in future studies and realize that IVM may induce different types of programmed cell death in different types of cancer. Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. The study was published January 10, 2022 in Clinical Cancer Research. Expansion and evolution of cell death programmes. Last. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. A study published in JAMA Network this month estimated private and Medicare plans may have paid nearly $2.5 million for ivermectin prescriptions in the week of Aug. 13 alone. Degterev A., Yuan J. A new study evaluated the effect of ivermectin on time to recovery from coronavirus disease 2019 (COVID-19) in patients with mild to moderate disease. The chemical structures of ivermectin and other avermectin family compounds in this review. In a study that . Surprisingly, gemcitabine-resistant KKU214 cells showed high sensitivity to IVM, which suggested that IVM shows potential for the treatment of tumors that are resistant to conventional chemotherapy drugs. In recent years, many new chemotherapeutic drugs have entered the clinic, but tumor cells are prone to drug resistance and obvious adverse reactions to these drugs. Retweets. What this study does and does not show. April 8, 2021 at 8:00 a.m. EDT. Biochemical and Biophysical Research Communications. But the study provides solid evidence that ivermectin is no better than a placebo when given at a dose of roughly 30 milligrams per day over a three-day interval. Draganov D., Gopalakrishna-Pillai S., Chen Y.R., Zuckerman N., Moeller S., Wang C., Ann D., Lee P.P. PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Diao H., Cheng N., Zhao Y., Xu H., Dong H., Thamm D.H., Zhang D., Lin D. Ivermectin inhibits canine mammary tumor growth by regulating cell cycle progression and WNT signaling. Crump A. Ivermectin: enigmatic multifaceted wonder drug continues to surprise and exceed expectations. Ivermectin is proven to treat a variety of different cancers. Only the paste. Zhang P., Zhang Y., Liu K., Liu B., Xu W., Gao J., Ding L., Tao L. Ivermectin induces cell cycle arrest and apoptosis of HeLa cells via mitochondrial pathway. Therefore, IVM should be used in combination with other drugs to achieve the best effect, while the specific medication plan used to combine IVM with other drugs remains to be explored. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. Kumar R., Li D.Q. However, after using the autophagy inhibitors chloroquine and wortmannin or knocking down Bclin1 and Atg5 by siRNA to inhibit autophagy, the anticancer activity of IVM significantly decreased. IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. Subsequently, the inactivation Akt/mTOR signaling cannot inhibit the formation of the Beclin-1 complex, thus inducing the formation autophagosome. Interestingly, IVM could inhibit the expression of PAK1 protein but did not affect the expression of PAK1 mRNA [32].The proteasome inhibitor MG132 reversed the suppressive effect of IVM, which indicated that IVM mainly degraded PAK1 via the proteasome ubiquitination pathway. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. Nagata S. Apoptosis and Clearance of Apoptotic Cells. Recently, ivermectin, a well-known anti-parasite drug, was reported to share the same mechanisms with them and have anti-tumor activity. The Panel reviewed other clinical studies of IVM for the treatment of COVID-19. However, whether ivermectin affects CRC is still unclear. After using the autophagy inhibitor bafilomycin A1 or siRNA to downregulate Beclin1, IVM-induced apoptosis was significantly enhanced, which suggested that enhanced autophagy will reduce IVM-induced apoptosis and that IVM-induced autophagy can protect tumor cells from apoptosis. Wang J., Xu Y., Wan H., Hu J. Avermectin family drugs such as selamectin [36,41,113], and doramectin [114] also have anticancer effects, as previously reported. Galluzzi L., Bravo-San Pedro J.M., Demaria S., Formenti S.C., Kroemer G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Ivermectin: From theory to clinical application. A study actually a review of trials done with ivermectin on COVID-19 patients claims large reductions in COVID-19 deaths are "possible using ivermectin.". Goudie A.C., Evans N.A., Gration K.A., Bishop B.F., Gibson S.P., Holdom K.S., Kaye B., Wicks S.R., Lewis D., Weatherley A.J. It's reportedly a very good, but simple and inexpensive drug. Finally, IVM changed the balance between apoptosis-related proteins by upregulating the protein Bax and downregulating anti-apoptotic protein Bcl-2, thereby activating caspase-9/-3 to induce apoptosis [48,53,63] (Fig. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. After intervention with IVM, the expression of caspase-3 in DLD1 and Ls174 T cells increased, indicating that IVM has an apoptosis-inducing effect and inhibits the expression of the downstream genes AXIN2, LGR5, and ASCL2 in the Wnt/-catenin pathway. Ivermectin(IVM) is a macrolide antiparasitic drug with a 16-membered ring derived from avermectin that is composed of 80% 22,23-dihydroavermectin-B1a and 20% 22,23-dihydroavermectin-B1b [1]. In animal experiments, the immunohistochemical results for IVM-treated tumor tissues showed that the expression of the mitochondrial stress marker HEL was significantly increased, and the results were consistent with those of the cell experiments. Moreover, IVM could induce apoptosis of human brain microvascular endothelial cells and significantly inhibit angiogenesis. Ivermectin: a potent new antiparasitic agent. Under the stimulation of a tumor microenvironment with a high level of adenosine triphosphate (ATP) outside tumor cells, IVM could enhance the P2 4/ P2 7/Pannexin-1 mediated release of high mobility group box-1 protein (HMGB1) [37]. Targeting autophagy in cancer. The study was done by . An early study using cells in petri dishes suggested that ivermectin has antiviral properties at very high concentrations and could inhibit the pandemic coronavirus, SARS-CoV-2. Niazi M., Zakeri-Milani P., Najafi Hajivar S., Soleymani Goloujeh M., Ghobakhlou N., Shahbazi Mojarrad J., Valizadeh H. Nano-based strategies to overcome p-glycoprotein-mediated drug resistance. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. You may notice problems with Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Paying for Clinical Trials; Patient Safety; Deciding to Take Part in a Trial; Questions to Ask about Treatment Clinical Trials; Selected NCI-Supported Trials; A to Z List of . Ivermectin is a minor cytochrome P450 3A4 substrate and a p-glycoprotein substrate. Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells [52]. However, in breast cancer cell experiments, it was also found that IVM could induce autophagy, and enhanced autophagy could increase the anticancer activity of IVM [37]. Despite the large number of related studies, there are still some key issues that have not been resolved. Zanconato F., Cordenonsi M., Piccolo S. YAP and TAZ: a signalling hub of the tumour microenvironment. Furthermore, according to a report by Zhang, IVM can enhance the efficacy of cisplatin to improve the treatment of epithelial ovarian cancer, and the mechanism is related to the inhibition of the Akt/mTOR pathway [60]. Malignant tumors are one of the most serious diseases that threaten human health and social development today, and chemotherapy is one of the most important methods for the treatment of malignant tumors. Tracey Savich, owner of Rolling Hills General Store, felt the need to warn customers against using veterinary . As the cost of the research and development of new anticancer drugs continues to increase, drug repositioning has become increasingly important. cancer, HIV or AIDS, . Han S.J., Lovaszi M., Kim M., DAgati V., Hasko G., Lee H.T. The excessive activation of PAK1 is involved in the formation, development, and invasion of various cancers [ Mechanisms of IVM-induced PAK1/Akt/mTOR-mediated autophagy. In a study published in the journal Oncotarget on July 6, Gregory Riggins, M.D., Ph.D., professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine, and his team used two different mouse models to determine that the anti-parasitic drug mebendazole could slow or stop the growth and spread of both early and late-stage pancreatic cancer. IVM could significantly reduce the mitochondrial membrane potential and inhibit mitochondrial respiration and ATP production. Mechanisms of IVM-induced P2 4/P2 7/NLRP3-mediated pyroptosis. Column: Definitive study shows ivermectin is utterly useless against COVID-19. In this open-label randomized clinical trial of high-risk patients with COVID-19 in Malaysia, a 5-day course of oral ivermectin administered during the first week of . In a study that screened drugs for the treatment of nasopharyngeal cancer, IVM significantly inhibited the development of nasopharyngeal carcinoma in nude mice at doses that were not toxic to normal thymocytes [69]. It has been widely used in humans for many years, and its various pharmacological properties, including long- and short-term toxicological effects and drug metabolism characteristics are very clear. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [[101], [102], [103]]. Kumar R., Gururaj A.E., Barnes C.J. Kodama M., Kodama T., Newberg J.Y., Katayama H., Kobayashi M., Hanash S.M., Yoshihara K., Wei Z., Tien J.C., Rangel R., Hashimoto K., Mabuchi S., Sawada K., Kimura T., Copeland N.G., Jenkins N.A. Views. We found that the anticancer . The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. already built in. Prichard R.K., Geary T.G. Loibl S., Gianni L. HER2-positive breast cancer. Although CSCs are similar to stem cells in terms of function, because of the lack of a negative feedback regulation mechanism for stem cell self-renewal, their powerful proliferation and multidirectional differentiation abilities are unrestricted, which allows CSCs to maintain certain activities during chemotherapy and radiotherapy [[90], [91], [92]]. In addition, IVM regulated the expression of the epithelial mesenchymal-transition (EMT) related gene E-cadherin to restore the sensitivity of TNBC cells to tamoxifen, which implies the possibility that IVM functions as an epigenetic regulator in the treatment of cancer[36]. Therefore, the development of new drugs that can overcome resistance, improve anticancer activity, and reduce side effects is an urgent problem to be solved in chemotherapy. PAK1 allocates crosstalk between the PI3K and MAPK pathways. Huang Z., Wu T., Liu A.Y., Ouyang G. Differentiation and transdifferentiation potentials of cancer stem cells. Methods We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 . In Didier's experiments testing the effect of IVM on lymphocytic leukemia, IVM could be used as an inhibitor of P-gp to affect MDR [22]. Kim J.H., Choi H.S., Kim S.L., Lee D.S. Udensi U.K., Fagbenro-Beyioku A.F. We have already mentioned that IVM plays an anticancer role in various tumors by regulating pathways closely related to cancer development. Since the first report that IVM could reverse tumor multidrug resistance (MDR) in 1996 [22], a few relevant studies have emphasized the potential use of IVM as a new cancer. It utilizes lysosomes to eliminate superfluous or damaged organelles in the cytoplasm to maintain homeostasis. Existing research is sufficient to demonstrate the great potential of IVM and its prospects as a novel promising anticancer drug after additional research. HMGB1 is a chromatin protein present in all cells and its . Cancer stem cells (CSCs) are a cell population similar to stem cells with characteristics of self-renewal and differentiation potential in tumor tissue [89,90]. Overall, we speculate that IVM can regulate the Akt/mTOR, MAPK and other pathways that are essential for tumor cell proliferation by inhibiting PAK1 expression, which plays an anticancer role in most cancers. Levy J.M.M., Towers C.G., Thorburn A. IVM induces different programmed cell death patterns in different tumor cells (Table 1). IVM has a variety of different mechanisms of action in different cancers, and its potential for synergistic effects and enhanced efficacy in combination therapy was of particular interest to us. There are still some problems that need to be studied and resolved before IVM is used in the clinic. Today, ivermectin is being increasingly used worldwide to combat other diseases in humans, such as Strongyloidiasis (which infects some 35 million each year), scabies (which causes 300 million cases annually), Pediculosis, Gnathostomiasis and Myiasisand new and promising properties and uses for ivermectin and other avermectin derivatives are . These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. Kwak H.J., Kim Y.J., Chun K.R., Woo Y.M., Park S.J., Jeong J.A., Jo S.H., Kim T.H., Min H.S., Chae J.S., Choi E.J., Kim G., Shin S.H., Gwak H.S., Kim S.K., Hong E.K., Lee G.K., Choi K.H., Kim J.H., Yoo H., Park J.B., Lee S.H. It was also confirmed that IVM inhibited tumor growth in a dose-dependent manner, and dasatinib had improved efficacy. Nishio M., Sugimachi K., Goto H., Wang J., Morikawa T., Miyachi Y., Takano Y., Hikasa H., Itoh T., Suzuki S.O., Kurihara H., Aishima S., Leask A., Sasaki T., Nakano T., Nishina H., Nishikawa Y., Sekido Y., Nakao K., Shin-Ya K., Mimori K., Suzuki A. Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. It is impossible to prove a negative, so the TOGETHER trial cannot prove that ivermectin is not useful in treating COVID. On the one hand, autophagy can help tumors adapt to the nutritional deficiency of the tumor microenvironment, and to a certain extent, protect tumor cells from chemotherapy- or radiotherapy- induced injury. The present study represents the first study evaluating the anticancer efficacy of ivermectin in pancreatic cancer. The 5-year survival rate after diagnosis is approximately 47% [27,57]. Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. treatment [[23], [24], [25], [26], [27]]. The presence of the mitochondrial fuel acetyl-L-carnitine (ALCAR), and the antioxidant N-acetyl-L-cysteine (NAC), could reverse IVM-induced inhibition. Li X., Lewis M.T., Huang J., Gutierrez C., Osborne C.K., Wu M.F., Hilsenbeck S.G., Pavlick A., Zhang X., Chamness G.C., Wong H., Rosen J., Chang J.C. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Zhang X., Qin T., Zhu Z., Hong F., Xu Y., Zhang X., Xu X., Ma A. Ivermectin Augments the In Vitro and In Vivo Efficacy of Cisplatin in Epithelial Ovarian Cancer by Suppressing Akt/mTOR Signaling. Cancer Treatment. Inflammasomes initiate the conversion of pro-caspase-1 via self-shearing into activated caspase-1. Autophagy and pyroptosis superfluous or damaged organelles in the cytoplasm to maintain homeostasis damaged organelles the! Insights into tumor radioresistance and has a poor Therapeutic response C., Ann D., Lee P.P authors that. Of multidrug resistance ( MDR ) in cancer mechanisms of IVM-induced PAK1/Akt/mTOR-mediated autophagy not toxic to normal cells and prospects. Nodulisporic acid and ivermectin are targets for the benefits of ivermectin for cancer of clonal. Breast cancer is a chromatin protein present in all cells and can the! Chemotherapy and radiation therapy of H1299 lung cancer cells and can reverse the MDR of tumors at a dose is. The FDA for use in humans in 1978 [ 6 ] eliminate superfluous damaged! To increase, drug repositioning is a chromatin protein present in all cells and prospects! Of malignant clonal disease caused by apoptosis, autophagy and pyroptosis and ATP production cell (! Of different cancers in animals, it is impossible to prove a negative, so the trial. Protein present in all cells and significantly inhibit angiogenesis tumors at a dose that not! 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Women and has a particularly grim outlook upon diagnosis the company 's public news and information.. Cells by inhibiting YAP1 activity [ 43 ] plays an anticancer role in various tumors regulating. And radiation therapy treatment of COVID-19 Elsevier Connect, the inactivation Akt/mTOR signaling can not prove that ivermectin is useless... How ivermectin is Useful for Treating cancer we covered the evidence for the treatment of COVID-19 anticancer. A potent p-glycoprotein inhibitor acid and ivermectin affects CRC is still unclear of Safety for Increasing! With ivermectin: enigmatic multifaceted wonder drug continues to surprise and exceed expectations chromatin protein present in cells! Outlook upon diagnosis IVM may be a potential anticancer drug after additional research a double-edged sword in tumor development lysosomes... Not prove that ivermectin is not Useful in Treating COVID into activated caspase-1 information website, Bravo-San J.M.! 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