Here’s something I have posted before. Google can not edit books.
Monkeypox can only be a serious problem for humans if it has been meddled with. For instance, GOF, ( gain of function )
The National Institute of Allergy and Infectious Diseases, directed by Dr. Anthony Fauci, last year paid $9.8 million to government researchers to test a monkeypox treatment. Some called the timing “curious” given the recent outbreak of the virus.
The National Institute of Allergy and Infectious Diseases (NIAID), directed by Dr. Anthony Fauci, last year paid $9.8 million to government researchers to test a monkeypox treatment, the National Pulse reported.
According to the National Institutes for Health (NIH), which oversees the NIAID, the research began Sept. 28, 2020 and will conclude Sept. 27, 2025. Its goal is to carry out a “randomized, placebo-controlled trial of the safety and efficacy of tecovirimat for the treatment of patients with monkeypox virus disease.” It is unclear if the grant provided for any payments in 2020.
The NIAID awarded the grant to the Frederick National Laboratory for Cancer Research, a federally funded research and development center in Frederick, Maryland, supported by the National Cancer Institute.
According to the grant abstract:
“The similarity between monkeypox and the variola [smallpox] virus, coupled with concerns about the potential of the variola virus as a potential bioterrorism agent, have placed monkeypox treatments at the forefront of public health and scientific research agendas in many countries.”
On May 25, SIGA Technologies Inc.announced that it received approval from the U.S. Food and Drug Administration (FDA) for an intravenous formulation of the antiviral tecovirimat (called TPOXX) for the treatment of smallpox.
Although smallpox was eradicated in 1980, the treatment was developed in the event smallpox were to be used as a bioweapon.
The U.S., Canada and Europe have approved an oral formulation of TPOXX for treating smallpox, and Europe also approved it for treating monkeypox and cowpox.
As of May 30, the NIH project had not generated any publicly available studies, papers or patents, according to The National Pulse.
The National Pulse called the timing of the grant “curious,” as it comes while pharmaceutical giants including Pfizer and Johson & Johnson are making record-level profits due to the COVID-19 pandemic.
Dr. Lori Dodd, a mathematical statistician in the biostatistics research branch of NIAID, is the project’s principal investigator.
On a recent segment of The Hill’s “Rising,” co-hosts Briahna Joy Gray and Kim Iversen reminded viewers that Dodd was “exposed for her involvement in the agency’s reported data altering of remdesivir trials to make [remdesivir] seem more effective against COVID.”
Iversen and Gray also found the timing of the funding suspicious.
“It could just be coincidental,” said Iversen, “ … but I will say that there is something very suspect about the fact that they started working on identifying treatments for monkeypox in September of 2020. This has been a virus that’s been around since 1970.”
However, Gray said, “in a world where everyone’s certainly concerned about viruses because of COVID-19, maybe the money simply started to flow in the fall of 2020.”
“What’s odd,” responded Iversen, “is that there’s now suddenly an outbreak [of monekypox] and that outbreak is making headlines and it’s spreading all around the world.”
Iversen implied the NIH may be hoping to develop a new treatment for monkeypox as public fear of the disease grows.
As The Defender has reported, others also questioned how unexpected the monkeypox outbreak was after learning about a March 2021 tabletop simulationof a hypothetical deadly outbreak of monkeypox predicted to occur in May 2022.
The National Pulse reported that a February 2022 peer-reviewed studyrevealed scientists performed a monkeypox-related gain-of-function research project at the Wuhan Institute of Virology in August 2021.
“Following the release of the Pfizer documents, it’s now confirmed that 1,223 people died within the first 28 days after being inoculated with the BioNTech Pfizer vaccine during trials — and it was still approved for use … If you want to read the documents yourself, you can do so by clicking here.
Far from being ‘safe and effective,’ Pfizer’s documents prove otherwise: the BioNTech Pfizer vaccine is perhaps the most ineffectual, dangerous ‘vaccine’ ever brought to market.
Besides slaughtering over 1,000 people in under a month, trials also produced hundreds of potentially fatal side effects, created fertility issues, and were only 12-15 per cent effective at preventing infection overall and subsequently dropped to less than 1 per cent — despite health officials claiming it would be over 90 per cent effective. They were lying … However, this should come as no surprise as Project Veritas previously caught Pfizer scientists admitting that natural immunity is ‘probably better than vaccination.’
The following is a condensed list of side effects found during Pfizer’s vaccine trials:
Myocarditis and other serious heart problems; liver failure; blood clotting; acute interstitial pneumonitis; a whole host of auto-immune disorders; various musculoskeletal and connective tissue disorders; gastrointestinal disorders; diabetes; herpes; thyroid disorders; several neurological conditions, including multiple sclerosis; blindness; seizures; epilepsy; narcolepsy; eczema; blisters; asthma; fertility problems; inflammatory bowel disease; Crohn’s disease; and Guillain-Barré Syndrome.”
There are hundreds of references at the end of this paper and it’s in plain sight on the NIH website 4/5/2022
Mingyang Tang, Xiaodong Hu, […], and Qiang Fang
Graphical abstract
Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Ivermectin induces apoptosis and autophagy is mutually regulated. Interestingly, ivermectin can also inhibit tumor stem cells and reverse multidrug resistance and exerts the optimal effect when used in combination with other chemotherapy drugs.
Abbreviations: ASC, Apoptosis-associated speck-like protein containing a CARD; ALCAR, acetyl-L-carnitine; CSCs, Cancer stem cells; DAMP, Damage-associated molecular pattern; EGFR, Epidermal growth factor receptor; EBV, Epstein-Barr virus; EMT, Epithelial mesenchymal-transition; GABA, Gamma-aminobutyric acid; GSDMD, Gasdermin D; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HER2, Human epidermal growth factor receptor 2; HMGB1, High mobility group box-1 protein; HSP27, Heat shock protein 27; LD50, median lethal dose; LDH, Lactate dehydrogenase; IVM, Ivermectin; MDR, Multidrug resistance; NAC, N-acetyl-L-cysteine; OCT-4, Octamer-binding protein 4; PAK1, P-21-activated kinases 1; PAMP, Pathogen-associated molecular pattern; PARP, poly (ADP- ribose) polymerase; P-gp, P-glycoprotein; PRR, pattern recognition receptor; ROS, Reactive oxygen species; STAT3, Signal transducer and activator of transcription 3; SID, SIN3-interaction domain; siRNA, small interfering RNA; SOX-2, SRY-box 2; TNBC, Triple-negative breast cancer; YAP1, Yes-associated protein 1
Chemical compounds reviewed in this article: ivermectin(PubChem CID：6321424), avermectin(PubChem CID：6434889), selamectin(PubChem CID：9578507), doramectin(PubChem CID：9832750), moxidectin(PubChem CID：9832912)
Keywords: ivermectin, cancer, drug repositioning
Abstract
Ivermectin is a macrolide antiparasitic drug with a 16-membered ring that is widely used for the treatment of many parasitic diseases such as river blindness, elephantiasis and scabies. Satoshi ōmura and William C. Campbell won the 2015 Nobel Prize in Physiology or Medicine for the discovery of the excellent efficacy of ivermectin against parasitic diseases. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. This suggests that ivermectin may be an anticancer drug with great potential. Here, we reviewed the related mechanisms by which ivermectin inhibited the development of different cancers and promoted programmed cell death and discussed the prospects for the clinical application of ivermectin as an anticancer drug for neoplasm therapy.
1. Introduction
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 addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [[2], [3], [4], [5]] (Fig. 1 ). IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. It has a good effect on the treatment of parasitic diseases such as river blindness, elephantiasis, and scabies. The discoverers of IVM, Japanese scientist Satoshi ōmura and Irish scientist William C. Campbell, won the Nobel Prize in Physiology or Medicine in 2015 [7,8]. 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]. IVM has also shown beneficial effects against other parasitic diseases, such as malaria [11,12], trypanosomiasis [13], schistosomiasis [14], trichinosis [15] and leishmaniasis [16].
The chemical structures of ivermectin and other avermectin family compounds in this review.
IVM not only has strong effects on parasites but also has potential antiviral effects. 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 α/β-mediated nuclear transport and exerts antiviral activity against the HIV-1 and dengue viruses [18]. Recent studies have also pointed out that it has a promising inhibitory effect on the SARS-CoV-2 virus, which has caused a global outbreak in 2020 [19]. In addition, IVM shows potential for clinical application in asthma [20] and neurological diseases [21]. Recently scientists have discovered that IVM has a strong anticancer effect.
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
treatment [[23], [24], [25], [26], [27]]. Despite the large number of related studies, there are still some key issues that have not been resolved. First of all, the specific mechanism of IVM-mediated cytotoxicity in tumor cells is unclear; it may be related to the effect of IVM on various signaling pathways, but it is not very clear overall. Second, IVM seems to induce mixed cell death in tumor cells, which is also a controversial issue. Therefore, this review summarized the latest findings on the anticancer effect of IVM and discussed the mechanism of the inhibition of tumor proliferation and the way that IVM induces tumor programmed cell death to provide a theoretical basis for the use of IVM as a potential anticancer drug. As the cost of the research and development of new anticancer drugs continues to increase, drug repositioning has become increasingly important. Drug repositioning refers to the development of new drug indications that have been approved for clinical use [28]. For some older drugs that are widely used for their original indications and have clinical data and safety information, drug repositioning allows them to be developed via a cheaper and faster cycle and to be used more effectively in clinical use clinically [29]. Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment.
2. The role of IVM in different cancers
2.1. Breast cancer
Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. The incidence of breast cancer has increased each year, and it has become one of the female malignant tumors with the highest incidence in globally. On average, a new case is diagnosed every 18 seconds worldwide [30,31]. After treatment with IVM, the proliferation of multiple breast cancer cell lines including MCF-7, MDA-MB-231 and MCF-10 was significantly reduced. The mechanism involved the inhibition by IVM of the Akt/mTOR pathway to induce autophagy and p-21-activated kinase 1(PAK1)was the target of IVM for breast cancer [32]. Furthermore, Diao’s study showed that IVM could inhibit the proliferation of the canine breast tumor cell lines CMT7364 and CIPp by blocking the cell cycle without increasing apoptosis, and the mechanism of IVM may be related to the inhibition of the Wnt pathway [33].
Triple-negative breast cancer (TNBC) refers to cancer that is negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2(HER2) and is the most aggressive subtype of breast cancer with the worst prognosis. In addition, there is also no clinically applicable therapeutic drug currently [34,35]. A drug screening study of TNBC showed that IVM could be used as a SIN3-interaction domain (SID) mimic to selectively block the interaction between SID and paired a-helix2. 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].
Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. 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]. However, the release of a large amount of HMGB1 into the extracellular environment will promote immune cell-mediated immunogenic death and inflammatory reactions, which will have an inhibitory effect on the growth of tumor cells. Therefore, we believe that the anticancer effect of IVM is not limited to cytotoxicity, but also involves the regulation of the tumor microenvironment. IVM regulates the tumor microenvironment and mediates immunogenic cell death, which may be a new direction for research exploring anticancer mechanisms in the future.
2.2. Digestive system cancer
Gastric cancer is one of the most common malignant tumors worldwide. In the past year, more than one million patients with gastric cancer have been diagnosed worldwide [38]. Nambara’s study showed that IVM could significantly inhibit the proliferation of gastric cancer cells in vivo and in vitro and that the inhibitory effect of IVM depended on the expression of Yes-associated protein 1(YAP1)[39]. The gastric cancer cell lines MKN1 and SH-10-TC have higher YAP1 expression than MKN7 and MKN28 cells, so MKN1 and SH-10-TC cells are sensitive to IVM, while MKN7 and MKN28 are not sensitive to IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment [40].
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 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/β-catenin pathway. However, the exact molecular target of IVM that affects the Wnt/β-catenin pathway remains to be explored.
Hepatocellular carcinoma is the fourth leading cause of cancer death worldwide. Approximately 80% of cases of liver cancer are caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection [42]. IVM could inhibit the development of hepatocellular carcinoma by blocking YAP1 activity in spontaneous liver cancer Mob1b-/-mice [43].Cholangiocarcinoma is a malignant tumor that originates in the bile duct inside and outside the liver. Intuyod’s experiment found that IVM inhibited the proliferation of KKU214 cholangiocarcinoma cells in a dose- and time-dependent manner [44]. IVM halted the cell cycle in S phase and promoted apoptosis. 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.
2.3. Urinary system cancer
Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. Its morbidity has increased by an average of 2% annually worldwide and the clinical treatment effect is not satisfactory [[45], [46], [47]]. Experiments confirmed that IVM could significantly inhibit the proliferation of five renal cell carcinoma cell lines without affecting the proliferation of normal kidney cells, and its mechanism may be related to the induction of mitochondrial dysfunction [48]. IVM could significantly reduce the mitochondrial membrane potential and inhibit mitochondrial respiration and ATP production. The presence of the mitochondrial fuel acetyl-L-carnitine (ALCAR), and the antioxidant N-acetyl-L-cysteine (NAC), could reverse IVM-induced inhibition. 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.
Prostate cancer is a malignant tumor derived from prostate epithelial cells, and its morbidity is second only to that of lung cancer among men in Western countries [49]. In Nappi’s experiment, it was found that IVM could enhance the drug activity of the anti-androgen drug enzalutamide in the prostate cancer cell line LNCaP and reverse the resistance of the prostate cancer cell line PC3 to docetaxel [50]. Interestingly, IVM also restored the sensitivity of the triple-negative breast cancer to the anti-estrogen drug tamoxifen [36], which also implies the potential for IVM to be used in endocrine therapy. Moreover, IVM was also found to have a good inhibitory effect on the prostate cancer cell line DU145 [51].
2.4. Hematological cancer
Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells [52]. In an experiment designed to screen potential drugs for the treatment of leukemia, IVM preferentially killed leukemia cells at low concentrations without affecting normal hematopoietic cells [51]. The mechanism was related to the increase in the influx of chloride ions into the cell by IVM, resulting in hyperpolarization of the plasma membrane and induction of reactive oxygen species (ROS) production. It was also proven that IVM has a synergistic effect with cytarabine and daunorubicin on the treatment of leukemia. Wang’s experiment found that IVM could selectively induce mitochondrial dysfunction and oxidative stress, causing chronic myeloid leukemia K562 cells to undergo increased caspase-dependent apoptosis compared with normal bone marrow cells [53]. It was also confirmed that IVM inhibited tumor growth in a dose-dependent manner, and dasatinib had improved efficacy.
2.5. Reproductive system cancer
Cervical cancer is one of the most common gynecological malignancies, resulting in approximately 530,000 new cases and 270,000 deaths worldwide each year. The majority of cervical cancers are caused by human papillomavirus (HPV) infection [54,55]. IVM has been proven to significantly inhibit the proliferation and migration of HeLa cells and promote apoptosis [56]. After intervention with IVM, the cell cycle of HeLa cells was blocked at the G1/S phase, and the cells showed typical morphological changes related to apoptosis.
Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. The 5-year survival rate after diagnosis is approximately 47% [27,57]. 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]. In research to screen potential targets for the treatment of ovarian cancer through the use of an shRNA library and a CRISPR/Cas9 library, the oncogene KPNB1 was detected. IVM could block the cell cycle and induce cell apoptosis through a KPNB1-dependent mechanism in ovarian cancer [59]. Interestingly, IVM and paclitaxel have a synergistic effect on ovarian cancer, and combined treatment in in vivo experiments almost completely inhibited tumor growth. 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].
2.6. Brain glioma
Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. Glioblastoma is the deadliest glioma, with a median survival time of only 14-17 months [61,62]. Experiments showed that IVM inhibited the proliferation of human glioblastoma U87 and T98 G cells in a dose-dependent manner and induced apoptosis in a caspase-dependent manner [63]. This was related to the induction of mitochondrial dysfunction and oxidative stress. Moreover, IVM could induce apoptosis of human brain microvascular endothelial cells and significantly inhibit angiogenesis. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. In another study, IVM inhibited the proliferation of U251 and C6 glioma cells by inhibiting the Akt/mTOR pathway [64].
In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion [65]. The DDX23 helicase activity affects the expression of miR-12 [66]. IVM could inhibit the DDX23/miR-12 signaling pathway by affecting the activity of DDX23 helicase, thereby inhibiting malignant biological behaviors. This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. However, here, we must emphasize that because IVM cannot effectively pass the blood-brain barrier [67], the prospect of the use of IVM in the treatment of gliomas is not optimistic.
2.7. Respiratory system cancer
Nasopharyngeal carcinoma is a malignant tumor derived from epithelial cells of the nasopharyngeal mucosa. The incidence is obviously regional and familial, and Epstein-Barr virus (EBV) infection is closely related [68]. 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]. In addition, IVM also had a cytotoxic effect on a variety of nasopharyngeal cancer cells in vitro, and the mechanism is related to the reduction of PAK1 kinase activity to inhibit the MAPK pathway.
Lung cancer has the highest morbidity and mortality among cancers [70]. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43]. 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 addition, IVM could reduce the metastasis of lung cancer cells by inhibiting EMT.
2.8. Melanoma
Melanoma is the most common malignant skin tumor with a high mortality rate. Drugs targeting BRAF mutations such as vemurafenib, dabrafenib and PD-1 monoclonal antibodies, including pembrolizumab and nivolumab have greatly improved the prognosis of melanoma [71,72]. Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity [73]. Interestingly, IVM could also show activity against BRAF wild-type melanoma cells, and its combination with dapafinib could significantly increase antitumor activity. Additionally, it has been confirmed that PAK1 is the key target of IVM that mediates its anti-melanoma activity, and IVM can also significantly reduce the lung metastasis of melanoma in animal experiments. Deng found that IVM could activate the nuclear translocation of TFE3 and induce autophagy-dependent cell death by dephosphorylation of TFE3 (Ser321) in SK-MEL-28 melanoma cells [74]. However, NAC reversed the effect of IVM, which indicated that IVM increased TFE3-dependent autophagy through the ROS signaling pathway.
3. IVM-induced programmed cell death in tumor cells and related mechanisms
3.1. Apoptosis
IVM induces different programmed cell death patterns in different tumor cells (Table 1). As shown in Table 1, the main form of IVM induced programmed cell death is apoptosis. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. The decrease in the mitochondrial membrane potential and the cytochrome c is released from mitochondria into the cytoplasm was detected after the intervention of IVM in Hela cells [56].Therefore, we infer that IVM induces apoptosis mainly through the mitochondrial pathway. In addition, morphological changed caused by apoptosis, including chromatin condensation, nuclear fragmentation, DNA fragmentation and apoptotic body formation were observed. 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. 2 ).
Mechanisms of IVM-induced mitochondria-mediated apoptosis.
3.2. Autophagy
Autophagy is a lysosomal-dependent form of programmed cell death. It utilizes lysosomes to eliminate superfluous or damaged organelles in the cytoplasm to maintain homeostasis. It is characterized by double-layered or multilayered vacuolar structures containing cytoplasmic components, which are known as autophagosomes [77]. In recent years, many studies have shown that autophagy is a double-edged sword in tumor development. 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. On the other hand, some autophagy activators can increase the sensitivity of tumors to radiotherapy and chemotherapy by inducing autophagy, and excessive activation of autophagy can also lead to tumor cell death [[78], [79], [80], [81]]. Overall, the specific environment of tumor cells will determine whether autophagy enhances or inhibits tumor development and improving autophagy activity has also become a new approach in cancer therapy. Programmed cell death mediated by autophagy after IVM intervention and the enhancement of the anticancer efficacy of IVM by regulating autophagy are interesting topics. Intervention with IVM in the breast cancer cell lines MCF-7 and MDA-MB-231 significantly increased intracellular autophagic flux and the expression of key autophagy proteins such as LC3, Bclin1, Atg5, and the formation of autophagosomes can be observed [32]. 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. This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. In addition, researchers also used the Akt activator CA-Akt to prove that IVM mainly induces autophagy by inhibiting the phosphorylation of Akt and mTOR (Fig. 3). The phenomenon of IVM-induced autophagy has also been reported in glioma and melanoma [ 64,74]. All of the above findings indicate the potential of IVM as an autophagy activator to induce autophagy-dependent death in tumor cells.
Mechanisms of IVM-induced PAK1/Akt/mTOR-mediated autophagy.
3.3. Cross talk between IVM-induced apoptosis and autophagy
The relationship between apoptosis and autophagy is very complicated, and the cross talk between the two plays a vital role in the development of cancer [82]. Obviously, the existing results suggest that IVM-induced apoptosis and autophagy also exhibit cross talk. For example, it was found in SK-MEL-28 melanoma cells that IVM can promote apoptosis as well as autophagy [74]. 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. 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]. The latest research shows that in normal circumstances autophagy will prevent the induction of apoptosis and apoptosis-related caspase enzyme activation will inhibit autophagy. However, in special circumstances, autophagy may also help to induce apoptosis or necrosis [83]. In short, the relationship between IVM-induced apoptosis and autophagy involves a complex regulatory mechanism, and the specific molecular mechanism needs further study. We believe that deeper exploration of the mechanism can further guide the use of IVM in the treatment of cancer.
3.4. Pyroptosis
Pyroptosis is a type of inflammatory cell death induced by inflammasomes. The inflammasome is a multimolecular complex containing pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. PRR can identify pathogen-associated molecular patterns (PAMPs) that are structurally stable and evolutionarily conserved on the surface of pathogenic microorganisms and damage-associated molecular patterns (DAMPs) produced by damaged cells [84,85]. Inflammasomes initiate the conversion of pro-caspase-1 via self-shearing into activated caspase-1. Activated caspase-1 can cause pro-IL-1β and pro-IL-18 to mature and to be secreted. Gasdermin D(GSDMD)is a substrate for activated caspase-1 and is considered to be a key protein in the execution of pyroptosis [86,87]. In an experiment by Draganov, it was found that the release of lactate dehydrogenase (LDH) and activated caspase-1 was significantly increased in breast cancer cells after IVM intervention [37]. In addition, characteristic pyroptosis phenomena such as cell swelling and rupturing were observed. The authors speculated that IVM may mediate the occurrence of pyroptosis via the P2 × 4/P2 × 7/NLRP3 pathway (Fig. 4), but there is no specific evidence to prove this speculation. Interestingly, in ischemia-reperfusion experiments, IVM aggravated renal ischemia via the P2 × 7/NLRP3 pathway and increased the release of proinflammatory cytokines in human proximal tubular cells [88]. 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.
Mechanisms of IVM-induced P2 × 4/P2 × 7/NLRP3-mediated pyroptosis.
4. Anticancer effect of IVM through other pathways
4.1. Cancer stem cells
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]. 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]]. When the external environment is suitable, CSCs will rapidly proliferate to reactivate the formation and growth of tumors. Therefore, CSCs have been widely recognized as the main cause of recurrence after treatment [93,94]. Guadalupe evaluated the effect of IVM on CSCs in the breast cancer cell line MDA-MB-231 [95]. The experimental results showed that IVM would preferentially targeted and inhibited CSCs-rich cell populations compared with other cell populations in MDA-MB-231 cells. 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. This suggests that IVM may be used as a potential CSCs inhibitor for cancer therapy. Further studies showed that IVM could inhibit CSCs by regulating the PAK1-STAT3 axis [96].
4.2. Reversal of tumor multidrug resistance
MDR of tumor cells is the main cause of relapses and deaths after chemotherapy [97]. ATP binding transport family-mediated drug efflux and overexpression of P-glycoprotein (P-gp) are widely considered to be the main causes of tumor MDR [[98], [99], [100]]. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [[101], [102], [103]]. 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]. In Jiang’s experiment, IVM reversed the drug resistance of the vincristine-resistant colorectal cancer cell line HCT-8, doxorubicin-resistant breast cancer cell line MCF-7 and the chronic myelogenous leukemia cell line K562 [104]. IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. Earlier, we mentioned the role of IVM in docetaxel-resistant prostate cancer [50] and gemcitabine-resistant cholangiocarcinoma [44]. These results indicated the significance of applying IVM for the treatment of chemotherapy patients with MDR.
4.3. Enhanced targeted therapy and combined treatment
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]. HSP27 is a molecular chaperone protein that is highly expressed in many cancers and associated with drug resistance and poor prognosis. It is considered as a new target for cancer therapy [107]. Recent studies have found that IVM could be used as an inhibitor of HSP27 phosphorylation to enhance the activity of anti-EGFR drugs in EGFR/HER2- driven tumors. An experiment found that IVM could significantly enhance the inhibitory effects of erlotinib and cetuximab on lung cancer and colorectal cancer [50]. Earlier, we mentioned that IVM combined with conventional chemotherapeutic drugs such as cisplatin [60], paclitaxel [59], daunorubicin and cytarabine [51], or with targeted drugs such as dasatinib [53] and dapafenib [73] shows great potential for cancer treatment. The combination of drugs can effectively increase efficacy, reduce toxicity or delay drug resistance. Therefore, combination therapy is the most common method of chemotherapy. 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. Not only does IVM not overlap with other therapies in term of its mechanism of action, but the fact that of IVM has multiple targets suggests that it is not easy to produce IVM resistance. Therefore, continued study and testing of safe and effective combination drug therapies is essential to maximize the anticancer effects of IVM.
5. Molecular targets and signaling pathways involved in the anticancer potential of IVM
As mentioned above, the anticancer mechanism of IVM involves a wide range of signaling pathways such as Wnt/β-catenin, Akt/mTOR, MAPK and other possible targets such as PAK1 and HSP27, as well as other mechanisms of action (Table 2 ). We found that IVM inhibits tumor cell development in a PAK1-dependent manner in most cancers. Consequently, we have concentrated on discussing the role of PAK1 kinase and cross-talk between various pathways and PAK1 to provide new perspectives on the mechanism of IVM function.
As a member of the PAK family of serine/threonine kinases, PAK1 has a multitude of biological functions such as regulating cell proliferation and apoptosis, cell movement, cytoskeletal dynamics and transformation [108]. Previous studies have indicated that PAK1 is located at the intersection of multiple signaling pathways related to tumorigenesis and is a key regulator of cancer signaling networks (Fig. 5). The excessive activation of PAK1 is involved in the formation, development, and invasion of various cancers [ 109,110]. Targeting PAK1 is a novel and promising method for cancer treatment, and the development of PAK1 inhibitors has attracted widespread attention [111]. IVM is a PAK1 inhibitor in a variety of tumors, and it has good safety compared to that of other PAK1 inhibitors such as IPA-3. In melanoma and nasopharyngeal carcinoma, IVM inhibited cell proliferation activity by inhibiting PAK1 to downregulate the expression of MEK 1/2 and ERK1/2 [69,73]. 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. 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. We have already mentioned that IVM plays an anticancer role in various tumors by regulating pathways closely related to cancer development. PAK1 is at the junction of these pathways. 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.
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. 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. 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. Drug repositioning is a shortcut to accelerate the development of anticancer drugs.
As mentioned above, the broad-spectrum antiparasitic drug IVM, which is widely used in the field of parasitic control, has many advantages that suggest that it is worth developing as a potential new anticancer drug. IVM selectively inhibits the proliferation of tumors at a dose that is not toxic to normal cells and can reverse the MDR of tumors. Importantly, IVM is an established drug used for the treatment of parasitic diseases such as river blindness and elephantiasis. 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. In healthy volunteers, the dose was increased to 2 mg/Kg, and no serious adverse reactions were found, while tests in animals such as mice, rats, and rabbits found that the median lethal dose (LD50) of IVM was 10-50 mg/Kg [112] In addition, IVM has also been proven to show good permeability in tumor tissues [50]. Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug. There are still some problems that need to be studied and resolved before IVM is used in the clinic.
(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. However, to date, no exact target for IVM action has been found. (2) IVM regulates the tumor microenvironment, inhibits the activity of tumor stem cells and reduces tumor angiogenesis and tumor metastasis. However, there is no systematic and clear conclusion regarding the related molecular mechanism. Therefore, in future research, it is necessary to continue to explore the specific mechanism of IVM involved in regulating the tumor microenvironment, angiogenesis and EMT. (3) It has become increasingly clear that IVM can induce a mixed cell death mode involving apoptosis, autophagy and pyroptosis depending on the cell conditions and cancer type. 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. (4) IVM can enhance the sensitivity of chemotherapeutic drugs and reduce the production of resistance. 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.
Most of the anticancer research performed on the avermectin family has been focused on avermectin and IVM until now. Avermectin family drugs such as selamectin [36,41,113], and doramectin [114] also have anticancer effects, as previously reported. With the development of derivatives of the avermectin family that are more efficient and less toxic, relevant research on the anticancer mechanism of the derivatives still has great value. Existing research is sufficient to demonstrate the great potential of IVM and its prospects as a novel promising anticancer drug after additional research. We believe that IVM can be further developed and introduced clinically as part of new cancer treatments in the near future.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
This work was supported by the Science Research Innovation Team Project of Anhui Colleges and Universities (2016-40), the Bengbu City Natural Science Foundation (2019-12), the Key Projects of Science Research of Bengbu Medical College (BYKY2019009ZD) and National University Students’ Innovation and Entrepreneurship Training Program (201910367001).
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The latest official Covid-19 figures from the Government of Canada are truly terrifying. They show that the double vaccinated population across Canada have now lost on average 74% of their immune system capability, and the triple vaccinated population across Canada have now lost on average 73% of their immune system capability compared to the natural immune system of unvaccinated people.
So much damage has now been done that the figures show the double vaccinated population are on average 3.8 times more likely to be infected with Covid-19 and 3.3 times more likely to die of Covid-19 than the unvaccinated population.
But it’s even worse for the triple vaccinated population in terms of their risk of death. The official figures show that they are on average 3.7 times more likely to be infected with Covid-19 but 5.1 times more likely to die of Covid-19 than the unvaccinated population.
These figures therefore suggest that both the double and triple vaccinated population in Canada have now had so much damage caused to their immune systems by the Covid-19 injections that they have now developed Acquired Immunodeficiency Syndrome.
The Canadian Covid-19 figures are produced by the Government of Canada (see here).
Their latest data is available as a downloadable pdf here.
The Government of Canada is publishing its official Covid-19 data in a way that makes it appear Canada is very much experiencing a ‘Pandemic of the Unvaccinated’, and that the Covid-19 vaccines are clearly effective. But this data is a fraud.
Page 20 onwards of the downloadable pdf contains data on Covid-19 cases, hospitalisations and deaths from the very start of the Covid-19 vaccination campaign in Canada on 14th Dec 20 all the way through to 27th Feb 22.
And it is this date parameter that makes the presented data extremely misleading, because there was a huge spike in Covid-19 cases, hospitalisations and deaths in January 2021 when just 0.3% of Canada were considered fully vaccinated.
But thanks to the gift of the ‘WayBackMachine’, we can look at previous Government of Canada Covid-19 Daily Epidemiology Update’ reports to deduce who is actually accounting for the majority of these deaths, hospitalisations and cases.
Here are the tables from the January 30th, February 6th, February 13th, February 20th, and February 27th, Government of Canada Covid-19 Daily Epidemiology Update’ reports showing the number of cases, hospitalisations and deaths by vaccination status from as far back as 14th December 2020, as well as the total population sizes of each vaccine group at the time of each report –
Now all we have to do is carry out simple subtraction to deduce who accounted for the majority of Covid-19 cases and when. The following chart shows the total number of Covid-19 cases per week by vaccination status across Canada between 31st Jan 22 and 27th Feb 22 –
Therefore, based on the figures provided by the Government of Canada in the tables above, here is a chart showing the population size by vaccination status across Canada each week between 31st Jan and 27th Feb 22 –
The unvaccinated population size is deduced by simply subtracting the total population size of those who’ve received at least one dose of Covid-19 Vaccine in Canada from the overall population size of 38.01 million. The double vaccinated population size is simply deduced by subtracting the triple vaccinated population size from the total population size of those who’ve received at least two doses in Canada.
As you can see the largest population size is actually the unvaccinated population, falling from 13.31 million in the week ending 6th Feb to 13.11 million in the week ending 27th Feb. Whereas the triple vaccinated population has increased from 10.9 million in the week ending 6th Feb to 12.9 million in the week ending 27th Feb.
So why on earth are there so many more cases among the double vaccinated and triple vaccinated population when –
a) They have a smaller population size than the unvaccinated? &
b) They have had a vaccine that allegedly reduces their risk of contracting Covid-19?
The answer is obvious. It’s because the Covid-19 vaccines damage the immune system and make recipients more likely to contract Covid-19.
The following chart shows the Covid-19 case-rate per 100,000 individuals by vaccination status across Canada per week between 31st Jan and 27th Feb 22 –
The case-rate is deduced by first dividing the total population size of each vaccine group by 100,000. The number of cases in each vaccine group is then divided by the answer to the previous equation to calculate the case-rate.
e.g. – 13.31 million / 100,000 = 133.1 6,932 cases / 133.1 = 52.08 cases per 100,000 individuals
As you can see the case rate has been astronomically higher among both the double and triple vaccinated since at least the 31st Jan 22. Now that we know the case-rates we can use Pfizer’s vaccine effectiveness formula to work out the real world Covid-19 vaccine effectiveness among both the double vaccinated and triple vaccinated populations.
That formula is –
Unvaccinated Case Rate – Vaccinated Case Rate / Unvaccinated Case Rate x 100 = Vaccine Effectiveness %
The following chart shows the real-world Covid-19 vaccine effectiveness across Canada among the double vaccinated and triple vaccinated population based on the case-rates above-
In the week ending 6th Feb the real-world vaccine effectiveness among the double vaccinated was an absolutely shocking minus-221.16%. But by the week ending 27th Feb this had fallen even further to minus 276.16%.
But the triple vaccinated population, whilst faring ever so slightly better, have seen a much steeper decline. In the week ending 6th Feb the real world vaccinated effectiveness among the triple vaccinated was still a shocking minus minus-197.79%. But by the week ending 27th Feb this had fallen to minus-269.87%.
This means that on average, the double vaccinated population are 3.8 times more likely to contract Covid-19 than the unvaccinated, and the triple vaccinated population are 3.7 times more likely to contract Covid-19 than the unvaccinated.
But vaccine effectiveness isn’t really a measure of a vaccine, it is a measure of a vaccine recipients immune system performance compared to the immune system performance of an unvaccinated person.
The Covid-19 vaccine is supposed to train your immune system to recognise the spike protein of the original strain of the Covid-19 virus. It does this by instructing your cells to produce the spike protein, then your immune system produces antibodies and remembers to use them later if you encounter the spike part of the Covid-19 virus again.
But the vaccine doesn’t hang around after it’s done the initial training, it leaves your immune system to take care of the rest. So when the authorities state that the effectiveness of the vaccines weaken over time, what they really mean is that the performance of your immune system weakens over time.
The problem we’re seeing here is that the immune system isn’t returning to its original and natural state. If it was then the outcomes of infection with Covid-19 would be similar to the outcomes among the not-vaccinated population.
Instead, it continues to decline at a rate that means the not-vaccinated population have a better performing immune system, so this means the Covid-19 injections are decimating the immune systems of the fully vaccinated.
The following chart shows the double vaccinated and triple vaccinated immune system performance across Canada vs the natural immune system performance of the unvaccinated population –
The immune system performance is calculated by using a slightly different calculation to the one used to equate vaccine effectiveness, which is as follows –
Unvaccinated case rate – Vaccinated case rate / LARGEST OF EITHER unvaccinated case rate OR vaccinated case rate X 100 = Immune System Performance % e.g. – Triple Vaccinated 21st Feb to 27th Feb = 22.83 – 84.44 / 84.44 x 100 = -72.96%
These figures show that the average double vaccinated Canadian has lost 73.42% of their immune system capability, meaning they are down to the last 26.58% of their immune system for fighting certain classes of viruses and certain cancers etc.
But unfortunately, the third jab hasn’t improved things because these figures show the average triple vaccinated Canadian has lost 72.96% of their immune system capability, meaning they are down to the last 27.04% of their immune system for fighting certain classes of viruses and certain cancers etc.
However, the figures provided by the Government of Canada are not separated by age-group, instead they provide overall figures for the entire population. And as we know, vaccine effectiveness (which is really immune system performance), is declining by the week.
Therefore, it’s perfectly plausible to assume that those who received the vaccine first will now be suffering much more severe immune system degradation than those who have only just received their second or third jab. And based on the following official figures on death, we propose that many double and triple vaccinated Canadian’s have surpassed the minus-90% to minus-100% immune system performance barrier, meaning they have essentially developed some new form of Covid-19 vaccine induced Acquired Immune Deficiency Syndrome.
The following chart shows the total number of Covid-19 deaths per week by vaccination status across Canada between 31st Jan 22 and 27th Feb 22 –
We have had to group the last two weeks together because the 27th Feb report showed less deaths in all vaccination groups than the 20th Feb report, with the exception of triple vaccinated who saw an increase. So we deduced the number of deaths between the 14th Feb report and 27th Feb report.
As you can see, just like with cases there have been far more deaths among both the double and triple vaccinated, but special attention should be paid to the final two weeks.
The following chart shows the population size by vaccination status across Canada between 31st Jan and 27th Feb 22 –
The following chart shows the Covid-19 death-rate per 100,000 individuals by vaccination status across Canada per week between 31st Jan and 27th Feb 22 based on the death figures and population size figures above –
As you cans see the death rate has been lowest among the unvaccinated since at least 31st Jan 22, and highest among the triple vaccinated population. But the death rates shown for 14th Feb to 27th Feb are deeply troubling.
The following chart shows the real-world Covid-19 vaccine effectiveness against death across Canada among the double vaccinated and triple vaccinated population based on the death-rates above-
In the week ending 6th Feb the real-world vaccine effectiveness among the double vaccinated was a troubling minus-10.79%. But by the week ending 27thFeb this had fallen to an absolutely shocking minus-228.52%.
But things are far worse for the triple vaccinated. In the week ending 6th Feb the real-world vaccine effectiveness among the triple vaccinated was a disturbing minus-57.25%. But by the week ending 27thFeb this had fallen to devastating minus-414.49%.
This means that on average, the double vaccinated population are 3.3 times more likely to die ofCovid-19 than the unvaccinated, but the triple vaccinated population are a shocking 5.1 times more likely to die of Covid-19 than the unvaccinated.
But don’t forget vaccine effectiveness isn’t really a measure of a vaccine, it is a measure of a vaccine recipients immune system performance compared to the immune system performance of an unvaccinated person.
The following chart shows the double vaccinated and triple vaccinated immune system performance against death across Canada vs the natural immune system performance of the unvaccinated population –
Double vaccinated individuals across Canada had an immune system performance of minus-69.56% by the 27th Feb 22, but triple vaccinated individuals across Canada had an immune system performance of minus-80.56%. This is what Covid-19 vaccination has done to the people of Canada.
AIDS (acquired immune deficiency syndrome) is the name used to describe a number of potentially life-threatening infections and illnesses that happen when your immune system has been severely damaged.
People with acquired immune deficiency syndrome are at an increased risk for developing certain cancers and for infections that usually occur only in individuals with a weak immune system.
Unfortunately, official Government of Canada data indicates that a large proportion of the double vaccinated and triple vaccinated population have now developed Acquired Immune Deficiency Syndrome, (AIDS) or a novel condition with similar attributes that can only be described as Covid-19 Vaccine Induced Acquired Immune Deficiency Syndrome (VAIDS).
A 33-fold spike has been witnessed in the occurrence of a blood clot in the lung, which can be fatal, in 30 days after getting infected with coronavirus, found a new study.
Another five-fold rise in the risk of getting deep vein thrombosis (DVT) has been linked with contracting Covid, it also said.
The findings of the research were published in the British Medical Journal on Thursday.
The study was carried out by Anne-Marie Fors Connolly of Umeå University in Sweden and her colleagues. The team looked to check the risk of DVT, pulmonary embolism, which is a blood clot in the lung, and other types of bleeding in over one million people, who were also the confirmed cases of Covid.
They also found a two-fold hike in the risk of bleeding after 30 days of the infection.
After becoming infected with coronavirus, patients remain at heightened risk of pulmonary embolism for six months. For bleeding and DVT, the risk is for two and three months, respectively.
“Pulmonary embolism can be fatal, so it is important to be aware [of this risk]. If you suddenly find yourself short of breath, and it doesn’t pass, [and] you’ve been infected with the coronavirus, then it might be an idea to seek help, because we find this increased risk for up to six months,” Connolly told the Guardian.
The World Health Organization’s international pandemic treaty signals the organization may be planning to seize power over health systems and push the world toward universal health coverage.
The globalist cabal is planning to monopolize health systems worldwide through the creation of an international pandemic treaty that makes the World Health Organization (WHO) the sole decision maker on pandemic matters.
The WHO may also be planning to seize power over health systems more broadly. Tedros Adhanom Ghebreyesus has stated that his “central priority” as director-general of the WHO is to push the world toward universal health coverage.
In the name of keeping everyone “safe” from infection, the globalist cabal has justified unprecedented attacks on democracy, civil liberties and personal freedoms, including the right to choose your own medical treatment.
Now, the WHO is gearing up to make its pandemic leadership permanent, and to extend it into the health care systems of every nation. The idea is to implement universal health care organized by the WHO as part of the Great Reset.
If this treaty goes through, the WHO would have the power to call for mandatory vaccinations and health passports, and its decision would supersede national and state laws.
Considering the WHO changed its definition of “pandemic” to “a worldwide epidemic of a disease,” removing the requirement of high morbidity, just about anything could be made to fit the pandemic criterion, including obesity.
The SMART Health Cards system is used by more than a dozen countries, 25 U.S. states, Puerto Rico and Washington, D.C.; the Australian Parliament is pushing a “Trusted Digital Identity Bill”; U.S. Congress is pushing the “Improving Digital Identity Act” and the WHO has signed a deal with a Deutsche Telekom subsidiary to build the first global digital vaccine passport.
All of these have one thing in common: the end goal, which is to expand them into a souped-up, global social credit system.
A new peer-reviewed study shows more than two-thirds of adolescents with COVID-19 vaccine-related myopericarditis had persistent heart abnormalities months after their initial diagnosis, raising concerns for potential long-term effects and contradicting claims by health officials that the condition is “mild.”
A new peer-reviewed study shows more than two-thirds of adolescents with COVID-19 vaccine-related myopericarditis had persistent heart abnormalities months after their initial diagnosis, raising concerns for potential long-term effects.
The findings, published March 25 in the Journal of Pediatrics, challenge the position of U.S. health agencies, including the Centers for Disease Control and Prevention (CDC), which claim heart inflammation associated with the Pfizer and Moderna mRNA vaccines is “mild.”
Researchers at Seattle Children’s Hospital reviewed cases of patients younger than 18 years old who presented to the hospital with chest pain and an elevated serum troponin level between April 1, 2021, and Jan. 7, 2022, within one week of receiving a second dose of Pfizer’s vaccine.
While 35 patients fit the criteria, 19 were excluded for various reasons. Cardiac magnetic resonance imaging (MRI) of the remaining 16 patients was performed three to eight months after they were first examined. The MRIs showed 11 had persistent late gadolinium enhancement(LGE), although levels were lower than in previous months.
According to the study, “The presence of LGE is an indicator of cardiac injury and fibrosis and has been strongly associated with worse prognosis in patients with classical acute myocarditis.”
In a meta-analysis of eight studies, LGE was found to be a predictor of all-cause death, cardiovascular death, cardiac transplant, rehospitalization, recurrent acute myocarditis and requirement for mechanical circulatory support.
Similarly, an 11-study meta-analysis found the “presence and extent of LGE to be a significant predictor of adverse cardiac outcomes.”
Researchers said that while symptoms “were transient and most patients appeared to respond to treatment,” the analysis showed a “persistence of abnormal findings.”
The results “rais[e] concerns for potential longer-term effects,” researchers wrote, adding that they plan to repeat imaging at one year after the vaccine to assess whether abnormalities have resolved.
“The paper provides more evidence that myocarditis in adolescents that result from COVID-19 vaccines is very serious,” said Dr. Madhava Setty, senior science editor for The Defender.
“All patients had significantly elevated serum troponin levels indicative of heart damage. And LGE, which is indicative of poor outcome, was present in more than two-thirds of the kids.”
The study stated, “All patients had elevated serum troponin levels (median 9.15 ng/mL, range 0.65-18.5, normal < 0.05 ng/mL).”
“These young patients had a median troponin level of 9.15 — more than 20 times greater than the levels found in people suffering heart attacks,” Setty said.
Commenting on the study, Dr. Marty Makary, surgeon and public policy researcher at Johns Hopkins University, tweeted “CDC has a civic duty to rigorously study the long-term effects of vaccine-induced myocarditis.”
CDC has a civic duty to do rigorously study the long-term effects of vaccine-induced myocarditis. New follow-up study 3-8 months after myocarditis shows the MRI heart abnormality of late gadolinium enhancement seen in 63% of children. Merits further study. https://t.co/klPVsnqrkc
Dr. Anish Koka, a cardiologist, told The Epoch Times the study suggests 60% to 70% of teenagers who get myocarditis from a COVID vaccine may be left with a scar on their heart.
“Certainly, children who had chest pain severe enough to merit seeking medical attention need to at least make sure they get a follow-up MRI,” Koka said, adding that the findings “should have clear implications for the discussion around vaccines, especially for high-risk male teenagers … and definitely for vaccine mandates.”
Myocarditis, or inflammation of the heart, is a severe and life-shortening disease. It was virtually unknown in young people until it became a recognized side effect of mRNA COVID vaccines, especially in boys and young men.
Pericarditis is inflammation of the pericardium, a sac-like structure with two layers of tissue that surrounds the heart to hold it in place and help it work.
According to the CDC, the most at-risk group is 16- and 17-year-old males, who have reported rates of 69 per million after the second dose of Pfizer’s COVID vaccine, although that number is likely underreported.
The CDC presentation also reported that in three-month follow-up evaluations, less than one-third of adolescents 12 to 17 who suffered vaccine-induced myocarditis (reported in Vaccine Safety DataLink) had fully recovered.
The 69-per-million rate the CDC uses to determine the incidence of myocarditis in 16- and 17-year-olds came from the agency’s Vaccine Adverse Event Reporting System (VAERS) — a U.S. government-run database that receives reports of vaccine adverse events.
One of the biggest limitations of passive surveillance systems, like VAERS, is that the system “receives reports for only a small fraction of adverse events,” according to the Department of Health and Human Services website.
This incidence matches nearly exactly with findings from a study that used the Vaccine Safety DataLink system, which showed 37.7 12- to 17-year-olds per 100,000 suffered myo/pericarditis after their second vaccine dose.
This indicates an incidence rate that is almost six times higher than the 69-per-million rate reported by the CDC.
In a preprint study from Kaiser Permanente, the incidence of myocarditis in 18- to 24-year-old males post-vaccination was even higher — at 537 per million, or 7.7 times higher than the statistics reported by the CDC.
No such thing as ‘mild’ heart damage
A paper published Jan. 14 in Circulation summarized the clinical course of 139 young patients between the ages of 12 and 20 who were hospitalized for myocarditis following COVID vaccination.
Of those patients, 19% were taken into intensive care, two required infusions of potent intravenous drugs used to raise critically low blood pressure and every patient had an elevated troponin level.
Troponin is an enzyme specific to cardiac myocytes. Levels above 0.4 ng/ml are strongly suggestive of heart damage.
The paper concluded, “Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms.”
“We suppose [a ‘mild clinical course] refers to the 81% who did not go to the ICU or the fact that none died or required ECMO (Extracorporeal Membrane Oxygenation, a desperate means to keep the body oxygenated when a patient’s heart or lungs have completely failed),” wrote Setty and Josh Mitteldorf, Ph.D., a theoretical physicist, in an articlecritiquing the Circulation paper.
“When does a ‘mild clinical course’ require hospitalization for a two-day median length of stay?” they asked. “How does anyone know if symptoms rapidly resolve?”
“We don’t know what it will do to young boys in the long term, especially since every patient had some damage to their heart as evidenced by significantly abnormal troponin levels,” Setty and Mitteldorf wrote. “And we don’t fully understand the mechanism by which the vaccines cause myocarditis.”
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