China puts on “digital handcuffs” to stop bank run “protesters” by controlling health passport. A perfect display of total state power evidencing why we have been fighting digital IDs and CBDCs with all of humanity’s strength.
SHANGHAI, May 18 (Reuters) – Three banks in China’s central Henan province have frozen at least $178 million of deposits, offering scant information on why or for how long, leaving firms unable to pay workers and individuals locked out of savings, depositors told Reuters.
Yu Zhou Xin Min Sheng Village Bank, Shangcai Huimin Country Bank and Zhecheng Huanghuai Community Bank froze all deposits on April 18, with all three telling customers they were upgrading internal systems. The banks have not issued any communication on the matter since, depositors said.
None of the three banks responded to Reuters’ emails or phone calls seeking comment.
While nominally small, China’s numerous local banks have outsized significance because they lend to small and mid-sized firms so their activity can be an indicator of the health of the economy, the world’s second-biggest after the United States.
Bank earnings and asset quality are widely expected to deteriorate due to reduced business activity brought about by strict COVID-19 containment measures, raising the prospect of economic contraction in the second quarter of the year.
Depositors of the three banks told Reuters they had been communicating with each other via messaging app WeChat about how to retrieve funds. Some posted screenshots of frozen accounts and shared conversations with bank staff.
Some posted videos of protests outside bank branches, while others said they had travelled to the banks’ headquarters in search of an explanation only to be turned away by police.
The China Banking and Insurance Regulatory Commision, which was cited in media reports on May 1 as saying it was looking into the matter, and the People’s Bank of China, the central bank, did not respond to faxed requests for comment.
Depositors from the southern Zhejiang province communicating over WeChat compiled a spreadsheet seen by Reuters in which they self-reported 1.2 billion yuan ($177.55 million) in frozen funds across the three banks.
As the banks have customers across China, magazine Caixin on April 30 reported the frozen amount could total $1.5 billion.
Jerry Chang, owner of a factory in Hubei province, cannot access his over 6 million yuan deposited at Yu Zhou Xin Min Sheng Village Bank.
“Not being able to withdraw money has a huge impact on the operation of our factory, including procurement and workers’ wages,” said Chang, who used the bank because of its marginally higher interest rate of 1.85%.
Tony Qian, an investment consultant from Zhejiang province, cannot access the 20 million yuan he put in Yu Zhou Xin Min Sheng Village Bank that he had been saving to buy property.
“The thing I’m most angry about is … no one has explained anything to us,” said Qian.
Russell L. Blaylock Additional article information
The COVID-19 pandemic is one of the most manipulated infectious disease events in history, characterized by official lies in an unending stream lead by government bureaucracies, medical associations, medical boards, the media, and international agencies.[3,6,57] We have witnessed a long list of unprecedented intrusions into medical practice, including attacks on medical experts, destruction of medical careers among doctors refusing to participate in killing their patients and a massive regimentation of health care, led by non-qualified individuals with enormous wealth, power and influence.
For the first time in American history a president, governors, mayors, hospital administrators and federal bureaucrats are determining medical treatments based not on accurate scientifically based or even experience based information, but rather to force the acceptance of special forms of care and “prevention”—including remdesivir, use of respirators and ultimately a series of essentially untested messenger RNA vaccines. For the first time in history medical treatment, protocols are not being formulated based on the experience of the physicians treating the largest number of patients successfully, but rather individuals and bureaucracies that have never treated a single patient—including Anthony Fauci, Bill Gates, EcoHealth Alliance, the CDC, WHO, state public health officers and hospital administrators.[23,38]
The media (TV, newspapers, magazines, etc), medical societies, state medical boards and the owners of social media have appointed themselves to be the sole source of information concerning this so-called “pandemic”. Websites have been removed, highly credentialed and experienced clinical doctors and scientific experts in the field of infectious diseases have been demonized, careers have been destroyed and all dissenting information has been labeled “misinformation” and “dangerous lies”, even when sourced from top experts in the fields of virology, infectious diseases, pulmonary critical care, and epidemiology. These blackouts of truth occur even when this information is backed by extensive scientific citations from some of the most qualified medical specialists in the world. Incredibly, even individuals, such as Dr. Michael Yeadon, a retired ex-Chief Scientist, and vice-president for the science division of Pfizer Pharmaceutical company in the UK, who charged the company with making an extremely dangerous vaccine, is ignored and demonized. Further, he, along with other highly qualified scientists have stated that no one should take this vaccine.
Dr. Peter McCullough, one of the most cited experts in his field, who has successfully treated over 2000 COVID patients by using a protocol of early treatment (which the so-called experts completely ignored), has been the victim of a particularly vicious assault by those benefiting financially from the vaccines. He has published his results in peer reviewed journals, reporting an 80% reduction in hospitalizations and a 75% reduction in deaths by using early treatment. Despite this, he is under an unrelenting series of attacks by the information controllers, none of which have treated a single patient.
Neither Anthony Fauci, the CDC, WHO nor any medical governmental establishment has ever offered any early treatment other than Tylenol, hydration and call an ambulance once you have difficulty breathing. This is unprecedented in the entire history of medical care as early treatment of infections is critical to saving lives and preventing severe complications. Not only have these medical organizations and federal lapdogs not even suggested early treatment, they attacked anyone who attempted to initiate such treatment with all the weapons at their disposal—loss of license, removal of hospital privileges, shaming, destruction of reputations and even arrest.
A good example of this outrage against freedom of speech and providing informed consent information is the recent suspension by the medical board in Maine of Dr. Meryl Nass’ medical license and the ordering of her to undergo a psychiatric evaluation for prescribing Ivermectin and sharing her expertise in this field.[9,65] I know Dr, Nass personally and can vouch for her integrity, brilliance and dedication to truth. Her scientific credentials are impeccable. This behavior by a medical licensing board is reminiscent of the methodology of the Soviet KGB during the period when dissidents were incarcerated in psychiatric gulags to silence their dissent.
OTHER UNPRECEDENTED ATTACKS
Another unprecedented tactic is to remove dissenting doctors from their positions as journal editors, reviewers and retracting of their scientific papers from journals, even after these papers have been in print. Until this pandemic event, I have never seen so many journal papers being retracted— the vast majority promoting alternatives to official dogma, especially if the papers question vaccine safety. Normally a submitted paper or study is reviewed by experts in the field, called peer review. These reviews can be quite intense and nit picking in detail, insisting that all errors within the paper be corrected before publication. So, unless fraud or some other major hidden problem is discovered after the paper is in print, the paper remains in the scientific literature.
We are now witnessing a growing number of excellent scientific papers, written by top experts in the field, being retracted from major medical and scientific journals weeks, months and even years after publication. A careful review indicates that in far too many instances the authors dared question accepted dogma by the controllers of scientific publications—especially concerning the safety, alternative treatments or efficacy of vaccines.[12,63] These journals rely on extensive adverting by pharmaceutical companies for their revenue. Several instances have occurred where powerful pharmaceutical companies exerted their influence on owners of these journals to remove articles that in any way question these companies’ products.[13,34,35]
Worse still is the actual designing of medical articles for promoting drugs and pharmaceutical products that involve fake studies, so-called ghostwritten articles.[49,64] Richard Horton is quoted by the Guardian as saying “journals have devolved into information laundering operations for the pharmaceutical industry.”[13,63] Proven fraudulent “ghostwritten” articles sponsored by pharmaceutical giants have appeared regularly in top clinical journals, such as JAMA, and New England Journal of Medicine—never to be removed despite proven scientific abuse and manipulation of data.[49,63]
Ghostwritten articles involve using planning companies whose job it is to design articles containing manipulated data to support a pharmaceutical product and then have these articles accepted by high-impact clinical journals, that is, the journals most likely to affect clinical decision making of doctors. Further, they supply doctors in clinical practice with free reprints of these manipulated articles. The Guardian found 250 companies engaged in this ghostwriting business. The final step in designing these articles for publication in the most prestigious journals is to recruit well recognized medical experts from prestigious institutions, to add their name to these articles. These recruited medical authors are either paid upon agreeing to add their name to these pre- written articles or they do so for the prestige of having their name on an article in a prestigious medical journal.
Of vital importance is the observation by experts in the field of medical publishing that nothing has been done to stop this abuse. Medical ethicists have lamented that because of this widespread practice “you can’t trust anything.” While some journals insist on disclosure information, most doctors reading these articles ignore this information or excuse it and several journals make disclosure more difficult by requiring the reader to find the disclosure statements at another location. Many journals do not police such statements and omissions by authors are common and without punishment.
As concerns the information made available to the public, virtually all the media is under the control of these pharmaceutical giants or others who are benefitting from this “pandemic”. Their stories are all the same, both in content and even wording. Orchestrated coverups occur daily and massive data exposing the lies being generated by these information controllers are hidden from the public. All data coming over the national media (TV, newspaper and magazines), as well as the local news you watch every day, comes only from “official” sources—most of which are lies, distortions or completely manufactured out of whole cloth—all aimed to deceive the public.
Television media receives the majority of its advertising budget from the international pharmaceutical companies—this creates an irresistible influence to report all concocted studies supporting their vaccines and other so-called treatments. In 2020 alone the pharmaceutical industries spent 6.56 billion dollars on such advertising.[13,14] Pharma TV advertising amounted to 4.58 billion, an incredible 75% of their budget. That buys a lot of influence and control over the media. World famous experts within all fields of infectious diseases are excluded from media exposure and from social media should they in any way deviate against the concocted lies and distortions by the makers of these vaccines. In addition, these pharmaceutical companies spend tens of millions on social media advertising, with Pfizer leading the pack with $55 million in 2020.
While these attacks on free speech are terrifying enough, even worse is the virtually universal control hospital administrators have exercised over the details of medical care in hospitals. These hirelings are now instructing doctors which treatment protocols they will adhere to and which treatments they will not use, no matter how harmful the “approved” treatments are or how beneficial the “unapproved” treatments are.[33,57]
Never in the history of American medicine have hospital administrators dictated to its physicians how they will practice medicine and what medications they can use. The CDC has no authority to dictate to hospitals or doctors concerning medical treatments. Yet, most physicians complied without the slightest resistance.
The federal Care Act encouraged this human disaster by offering all US hospitals up to 39,000 dollars for each ICU patient they put on respirators, despite the fact that early on it was obvious that the respirators were a major cause of death among these unsuspecting, trusting patients. In addition, the hospitals received 12,000 dollars for each patient that was admitted to the ICU—explaining, in my opinion and others, why all federal medical bureaucracies (CDC, FDA, NIAID, NIH, etc) did all in their power to prevent life- saving early treatments. Letting patients deteriorate to the point they needed hospitalization, meant big money for all hospitals. A growing number of hospitals are in danger of bankruptcy, and many have closed their doors, even before this “pandemic”. Most of these hospitals are now owned by national or international corporations, including teaching hospitals.
It is also interesting to note that with the arrival of this “pandemic” we have witnessed a surge in hospital corporate chains buying up a number of these financially at-risk hospitals.[1,54] It has been noted that billions in Federal Covid aid is being used by these hospital giants to acquire these financially endangered hospitals, further increasing the power of corporate medicine over physician independence. Physicians expelled from their hospitals are finding it difficult to find other hospitals staffs to join since they too may be owned by the same corporate giant. As a result, vaccine mandate policies include far larger numbers of hospital employees. For example, Mayo Clinic fired 700 employees for exercising their right to refuse a dangerous, essentially untested experimental vaccine.[51,57] Mayo Clinic did this despite the fact that many of these employees worked during the worst of the epidemic and are being fired when the Omicron variant is the dominant strain of the virus, has the pathogenicity of a common cold for most and the vaccines are ineffective in preventing the infection.
In addition, it has been proven that the vaccinated asymptomatic person has a nasopharyngeal titer of the virus as high as an infected unvaccinated person. If the purpose of the vaccine mandate is to prevent viral spread among the hospital staff and patients, then it is the vaccinated who present the greatest risk of transmission, not the unvaccinated. The difference is that a sick unvaccinated person would not go to work, the asymptomatic vaccinated spreader will.
What we do know is that major medical centers, such as Mayo Clinic, receive tens of millions of dollars in NIH grants each year as well as monies from the pharmaceutical makers of these experimental “vaccines”. In my view, that is the real consideration driving these policies. If this could be proven in a court of law the administrators making these mandates should be prosecuted to the fullest extent of the law and sued by all injured parties.
The hospital bankruptcy problem has grown increasingly acute due to hospitals vaccine mandates and resulting large number of hospitals staff, especially nurses, refusing to be forcibly vaccinated.[17,51] This is all unprecedented in the history of medical care. Doctors within hospitals are responsible for the treatment of their individual patients and work directly with these patients and their families to initiate these treatments. Outside organizations, such as the CDC, have no authority to intervene in these treatments and to do so exposes the patients to grave errors by an organization that has never treated a single COVID-19 patient.
When this pandemic started, hospitals were ordered by the CDC to follow a treatment protocol that resulted in the deaths of hundreds of thousands of patients, most of whom would have recovered had proper treatments been allowed.[43,44] The majority of these deaths could have been prevented had doctors been allowed to use early treatment with such products as Ivermectin, hydroxy-chloroquine and a number of other safe drugs and natural compounds. It has been estimated, based on results by physicians treating the most covid patients successfully, that of the 800,000 people that we are told died from Covid, 640,000 could have not only been saved, but could have, in many cases, returned to their pre-infection health status had mandated early treatment with these proven methods been used. This neglect of early treatment constitutes mass murder. That means 160,000 would have actually died, far less than the number dying at the hands of bureaucracies, medical associations and medical boards that refused to stand up for their patients. According to studies of early treatment of thousands of patients by brave, caring doctors, seventy-five to eighty percent of the deaths could have been prevented.[43,44]
Incredibly, these knowledgeable doctors were prevented from saving these Covid-19 infected people. It should be an embarrassment to the medical profession that so many doctors mindlessly followed the deadly protocols established by the controllers of medicine.
One must also keep in mind that this event never satisfied the criteria for a pandemic. The World Health Organization changed the criteria to make this a pandemic. To qualify for a pandemic status the virus must have a high mortality rate for the vast majority of people, which it didn’t (with a 99.98% survival rate), and it must have no known existing treatments—which this virus had—in fact, a growing number of very successful treatments.
The draconian measures established to contain this contrived “pandemic” have never been shown to be successful, such as masking the public, lockdowns, and social distancing. A number of carefully done studies during previous flu seasons demonstrated that masks, of any kind, had never prevented the spread of the virus among the public.
In fact, some very good studies suggested that the masks actually spread the virus by giving people a false sense of security and other factors, such as the observation that people were constantly breaking sterile technique by touching their mask, improper removal and by leakage of infectious aerosols around the edges of the mask. In addition masks were being disposed of in parking lots, walking trails, laid on tabletops in restaurants and placed in pockets and purses.
Within a few minutes of putting on the mask, a number of pathogenic bacteria can be cultured from the masks, putting the immune suppressed person at a high risk of bacterial pneumonia and children at a higher risk of meningitis. A study by researchers at the University of Florida cultured over 11 pathogenic bacteria from the inside of the mask worn by children in schools.
It was also known that children were at essentially no risk of either getting sick from the virus or transmitting it.
In addition, it was also known that wearing a mask for over 4 hours (as occurs in all schools) results in significant hypoxia (low blood oxygen levels) and hypercapnia (high CO2 levels), which have a number of deleterious effects on health, including impairing the development of the child’s brain.[4,72,52]
We have known that brain development continues long after the grade school years. A recent study found that children born during the “pandemic” have significantly lower IQs—yet school boards, school principals and other educational bureaucrats are obviously unconcerned.
TOOLS OF THE INDOCTRINATION TRADE
The designers of this pandemic anticipated a pushback by the public and that major embarrassing questions would be asked. To prevent this, the controllers fed the media a number of tactics, one of the most commonly used was and is the “fact check” scam. With each confrontation with carefully documented evidence, the media “fact checkers” countered with the charge of “misinformation”, and an unfounded “conspiracy theory” charge that was, in their lexicon, “debunked”. Never were we told who the fact checkers were or the source of their “debunking” information—we were just to believe the “fact checkers”. A recent court case established under oath that facebook “fact checkers” used their own staff opinion and not real experts to check “facts”. When sources are in fact revealed they are invariably the corrupt CDC, WHO or Anthony Fauci or just their opinion. Here is a list of things that were labeled as “myths” and “misinformation” that were later proven to be true.
The asymptomatic vaccinated are spreading the virus equally as with unvaccinated symptomatic infected.
The vaccines cannot protect adequately against new variants, such as Delta and Omicron.
Natural immunity is far superior to vaccine immunity and is most likely lifelong.
Vaccine immunity not only wanes after several months, but all immune cells are impaired for prolonged periods, putting the vaccinated at a high risk of all infections and cancer.
COVID vaccines can cause a significant incidence of blood clots and other serious side effects
The vaccine proponents will demand numerous boosters as each variant appears on the scene.
Fauci will insist on the covid vaccine for small children and even babies.
Vaccine passports will be required to enter a business, fly in a plane, and use public transportation
There will be internment camps for the unvaccinated (as in Australia, Austria and Canada)
The unvaccinated will be denied employment.
There are secret agreements between the government, elitist institutions, and vaccine makers
Many hospitals were either empty or had low occupancy during the pandemic.
The spike protein from the vaccine enters the nucleus of the cell, altering cell DNA repair function.
Hundreds of thousands have been killed by the vaccines and many times more have been permanently damaged.
Early treatment could have saved the lives of most of the 700,000 who died.
Vaccine-induced myocarditis (which was denied initially) is a significant problem and clears over a short period.
Special deadly lots (batches) of these vaccines are mixed with the mass of other Covid-19 vaccines
Several of these claims by those opposing these vaccines now appear on the CDC website—most still identified as “myths”. Today, extensive evidence has confirmed that each of these so-called “myths” were in fact true. Many are even admitted by the “saint of vaccines”, Anthony Fauci. For example, we were told, even by our cognitively impaired President, that once the vaccine was released all the vaccinated people could take off their masks. Oops! We were told shortly afterward— the vaccinated have high concentrations (titers) of the virus in their noses and mouths (nasopharynx) and can transmit the virus to others in which they come into contact—especially their own family members. On go the masks once again— in fact double masking is recommended. The vaccinated are now known to be the main superspreaders of the virus and hospitals are filled with the sick vaccinated and people suffering from serious vaccine complications.[27,42,45]
Another tactic by the vaccine proponents is to demonize those who reject being vaccinated for a variety of reasons. The media refers to these critically thinking individuals as “anti-vaxxers”, “vaccine deniers”, “Vaccine resisters”, “murders”, “enemies of the greater good” and as being the ones prolonging the pandemic. I have been appalled by the vicious, often heartless attacks by some of the people on social media when a parent or loved one relates a story of the terrible suffering and eventual death, they or their loved one suffered as a result of the vaccines. Some psychopaths tweet that they are glad that the loved one died or that the dead vaccinated person was an enemy of good for telling of the event and should be banned. This is hard to conceptualize. This level of cruelty is terrifying, and signifies the collapse of a moral, decent, and compassionate society.
It is bad enough for the public to sink this low, but the media, political leaders, hospital administrators, medical associations and medical licensing boards are acting in a similar morally dysfunctional and cruel way.
LOGIC, REASONING, AND SCIENTIFIC EVIDENCE HAS DISAPPEARED IN THIS EVENT
Has scientific evidence, carefully done studies, clinical experience and medical logic had any effect on stopping these ineffective and dangerous vaccines? Absolutely not! The draconian efforts to vaccinate everyone on the planet continues (except the elite, postal workers, members of Congress and other insiders).[31,62]
In the case of all other drugs and previous conventional vaccines under review by the FDA, the otherwise unexplained deaths of 50 or less individuals would result in a halt in further distribution of the product, as happened on 1976 with the swine flu vaccine. With over 18,000 deaths being reported by the VAERS system for the period December 14, 2020 and December 31st, 2021 as well as 139,126 serious injuries (including deaths) for the same period there is still no interest in stopping this deadly vaccine program. Worse, there is no serious investigation by any government agency to determine why these people are dying and being seriously and permanently injured by these vaccines.[15,67] What we do see is a continuous series of coverups and evasions by the vaccine makers and their promoters.
The war against effective cheap and very safe repurposed drugs and natural compounds, that have proven beyond all doubt to have saved millions of lives all over the world, has not only continued but has stepped up in intensity.[32,34,43]
Doctors are told they cannot provide these life-saving compounds for their patients and if they do, they will be removed from the hospital, have their medical license removed or be punished in many other ways. A great many pharmacies have refused to fill prescriptions for lvermectin or hydroxy- chloroquine, despite the fact that millions of people have taken these drugs safely for over 60 years in the case of hydroxy chloroquine and decades for Ivermectin.[33,36] This refusal to fill prescriptions is unprecedented and has been engineered by those wanting to prevent alternative methods of treatment, all based on protecting vaccine expansion to all. Several companies that make hydroxy chloroquine agreed to empty their stocks of the drug by donating them to the Strategic National Stockpile, making this drug far more difficult to get. Why would the government do that when over 30 well-done studies have shown that this drug reduced deaths anywhere from 66% to 92% in other countries, such as India, Egypt, Argentina, France, Nigeria, Spain, Peru, Mexico, and others?
The critics of these two life-saving drugs are most often funded by Bill Gates and Anthony Fauci, both of which are making millions from these vaccines.[48,15]
To further stop the use of these drugs, the pharmaceutical industry and Bill Gates/Anthony Fauci funded fake research to make the case that hydroxy chloroquine was a dangerous drug and could damage the heart. To make this fraudulent case the researchers administered the sickest of covid patients a near lethal dose of the drug, in a dose far higher than used on any covid patient by Dr. Kory, McCullough and other “real”, and compassionate doctors, physicians who were actually treating covid patients.
The controlled, lap-dog media, of course, hammered the public with stories of the deadly effect of hydroxy- chloroquine, all with a terrified look of fake panic. All these stories of ivermectin dangers were shown to be untrue and some of the stories were incredibly preposterous.[37,43]
The attack on Ivermectin was even more vicious than against hydroxy-chloroquine. All of this, and a great deal more is meticulously chronicled in Robert Kennedy, Jr’s excellent new book—The Real Anthony Fauci. Bill Gates, Big Pharma, and the Global War on Democracy and Public Health. If you are truly concerned with the truth and with all that has occurred since this atrocity started, you must not only read, but study this book carefully. It is fully referenced and covers all topics in great detail. This is a designed human tragedy of Biblical proportions by some of the most vile, heartless, psychopaths in history.
Millions have been deliberately killed and crippled, not only by this engineered virus, but by the vaccine itself and by the draconian measures used by these governments to “control the pandemic spread”. We must not ignore the “deaths by despair” caused by these draconian measures, which can exceed hundreds of thousands. Millions have starved in third world countries as a result. In the United States alone, of the 800,000 who died, claimed by the medical bureaucracies, well over 600,000 of these deaths were the result of the purposeful neglect of early treatment, blocking the use of highly effective and safe repurposed drugs, such as hydroxy-chloroquine and Ivermectin, and the forced use of deadly treatments such as remdesivir and use of ventilators. This does not count the deaths of despair and neglected medical care caused by the lockdown and hospital measures forced on healthcare systems.
To compound all this, because of vaccine mandates among all hospital personnel, thousands of nurses and other hospital workers have resigned or been fired.[17,30,51] This has resulted in critical shortages of these vital healthcare workers and dangerous reductions of ICU beds in many hospitals. In addition, as occurred in the Lewis County Healthcare System, a specialty-hospital system in Lowville, N.Y., closed its maternity unit following the resignation of 30 hospital staff over the state’s disastrous vaccine mandate orders. The irony in all these cases of resignations is that the administrators unhesitatingly accepted these mass staffing losses despite rantings about suffering from short staffing during a “crisis”. This is especially puzzling when we learned that the vaccines did not prevent viral transmission and the present predominant variant is of extremely low pathogenicity.
DANGERS OF THE VACCINES ARE INCREASINGLY REVEALED BY SCIENCE
While most researchers, virologists, infectious disease researchers and epidemiologists have been intimidated into silence, a growing number of high integrity individuals with tremendous expertise have come forward to tell the truth—that is, that these vaccines are deadly.
Most new vaccines must go through extensive safety testing for years before they are approved. New technologies, such as the mRNA and DNA vaccines, require a minimum of 10 years of careful testing and extensive follow-up. These new so-called vaccines were “tested” for only 2 months and then the results of these safety test were and continue to be kept secret. Testimony before Senator Ron Johnson by several who participated in the 2 months study indicates that virtually no follow-up of the participants of the pre-release study was ever done. Complains of complications were ignored and despite promises by Pfizer that all medical expenses caused by the “vaccines” would be paid by Pfizer, these individuals stated that none were paid. Some medical expenses exceed 100,000 dollars.
As an example of the deception by Pfizer, and the other makers of mRNA vaccines, is the case of 12-year-old Maddie de Garay, who participated in the Pfizer vaccine pre-release safety study. At Sen. Johnson’s presentation with the families of the vaccine injured, her mother told of her child’s recurrent seizures, that she is now confined to a wheelchair, must be tube fed and suffers permanent brain damage. On the Pfizer safety evaluation submitted to the FDA her only side effect is listed as having a “stomachache”. Each person submitted similar horrifying stories.
The Japanese resorted to a FOIA (Freedom of Information Act) lawsuit to force Pfizer to release its secret biodistribution study. The reason Pfizer wanted it kept secret is that it demonstrated that Pfizer lied to the public and the regulatory agencies about the fate of the injected vaccine contents (the mRNA enclosed nano-lipid carrier). They claimed that it remained at the site of the injection (the shoulder), when in fact their own study found that it rapidly spread throughout the entire body by the bloodstream within 48 hours.
The study also found that these deadly nano-lipid carriers collected in very high concentrations in several organs, including the reproductive organs of males and females, the heart, the liver, the bone marrow, and the spleen (a major immune organ). The highest concentration was in the ovaries and the bone marrow. These nano-lipid carriers also were deposited in the brain.
Dr. Ryan Cole, a pathologist from Idaho reported a dramatic spike in highly aggressive cancers among vaccinated individuals, (not reported in the Media). He found a frighteningly high incidence of highly aggressive cancers in vaccinated individuals, especially highly invasive melanomas in young people and uterine cancers in women. Other reports of activation of previously controlled cancers are also appearing among vaccinated cancer patients. Thus far, no studies have been done to confirm these reports, but it is unlikely such studies will be done, at least studies funded by grants from the NIH.
The high concentration of spike proteins found in the ovaries in the biodistribution study could very well impair fertility in young women, alter menstruation, and could put them at an increased risk of ovarian cancer. The high concentration in the bone marrow, could also put the vaccinated at a high risk of leukemia and lymphoma. The leukemia risk is very worrisome now that they have started vaccinating children as young as 5 years of age. No long-term studies have been conducted by any of these makers of Covid-19 vaccines, especially as regards the risk of cancer induction. Chronic inflammation is intimately linked to cancer induction, growth and invasion and vaccines stimulate inflammation.
Cancer patients are being told they should get vaccinated with these deadly vaccines. This, in my opinion, is insane. Newer studies have shown that this type of vaccine inserts the spike protein within the nucleus of the immune cells (and most likely many cell types) and once there, inhibits two very important DNA repair enzymes, BRCA1 and 53BP1, whose duty it is to repair damage to the cell’s DNA. Unrepaired DNA damage plays a major role in cancer.
There is a hereditary disease called xeroderma pigmentosum in which the DNA repair enzymes are defective. These ill-fated individuals develop multiple skin cancers and a very high incidence of organ cancer as a result. Here we have a vaccine that does the same thing, but to a less extensive degree.
One of the defective repair enzymes caused by these vaccines is called BRCA1, which is associated with a significantly higher incidence of breast cancer in women and prostate cancer in men.
It should be noted that no studies were ever done on several critical aspects of this type of vaccine.
They have never been tested for long term effects
They have never been tested for induction of autoimmunity
They have never been properly tested for safety during any stage of pregnancy
No follow-up studies have been done on the babies of vaccinated women
There are no long-term studies on the children of vaccinated pregnant women after their birth (Especially as neurodevelopmental milestone occur).
It has never been tested for effects on a long list of medical conditions:
Induction of autism spectrum disorders and schizophrenia
Long term immune function
Vertical transmission of defects and disorders
Previous experience with the flu vaccines clearly demonstrates that the safety studies done by researchers and clinical doctors with ties to pharmaceutical companies were essentially all either poorly done or purposefully designed to falsely show safety and coverup side effects and complications. This was dramatically demonstrated with the previously mentioned phony studies designed to indicate that hydroxy Chloroquine and Ivermectin were ineffective and too dangerous to use.[34,36,37] These fake studies resulted in millions of deaths and severe health disasters worldwide. As stated, 80% of all deaths were unnecessary and could have been prevented with inexpensive, safe repurposed medications with a very long safety history among millions who have taken them for decades or even a lifetime.[43,44]
It is beyond ironic that those claiming that they are responsible for protecting our health approved a poorly tested set of vaccines that has resulted in more deaths in less than a year of use than all the other vaccines combined given over the past 30 years. Their excuse when confronted was—“we had to overlook some safety measures because this was a deadly pandemic”.[28,46]
In 1986 President Reagan signed the National Childhood Vaccine Injury Act, which gave blanket protection to pharmaceutical makers of vaccines against injury litigation by families of vaccine injured individuals. The Supreme Court, in a 57-page opinion, ruled in favor of the vaccine companies, effectively allowing vaccine makers to manufacture and distribute dangerous, often ineffective vaccines to the population without fear of legal consequences. The court did insist on a vaccine injury compensation system which has paid out only a very small number of rewards to a large number of severely injured individuals. It is known that it is very difficult to receive these awards. According to the Health Resources and Services Administration, since 1988 the Vaccine Injury Compensation Program (VICP) has agreed to pay 3,597 awards among 19,098 vaccine injured individuals applying amounting to a total sum of $3.8 billion. This was prior to the introduction of the Covid-19 vaccines, in which the deaths alone exceed all deaths related to all the vaccines combined over a thirty-year period.
In 2018 President Trump signed into law the “right-to-try” law which allowed the use of experimental drugs and all unconventional treatments to be used in cases of extreme medical conditions. As we have seen with the refusal of many hospitals and even blanket refusal by states to allow Ivermectin, hydroxy-chloroquine or any other unapproved “official” methods to treat even terminal Covid-19 cases, these nefarious individuals have ignored this law.
Strangely, they did not use this same logic or the law when it came to Ivermectin and Hydroxy Chloroquine, both of which had undergone extensive safety testing by over 30 clinical studies of a high quality and given glowing reports on both efficacy and safety in numerous countries. In addition, we had a record of use for up to 60 years by millions of people, using these drugs worldwide, with an excellent safety record. It was obvious that a group of very powerful people in conjunction with pharmaceutical conglomerates didn’t want the pandemic to end and wanted vaccines as the only treatment option. Kennedy’s book makes this case using extensive evidence and citations.[14,32]
Dr. James Thorpe, an expert in maternal-fetal medicine, demonstrates that these covoid-19 vaccines given during pregnancy have resulted in a 50-fold higher incidence of miscarriage than reported with all other vaccines combined. When we examine his graph on fetal malformations there was a 144-fold higher incidence of fetal malformation with the Covid-19 vaccines given during pregnancy as compared to all other vaccines combined. Yet, the American Academy of Obstetrics and Gynecology and the American College of Obstetrics and Gynecology endorse the safety of these vaccines for all stages of pregnancy and among women breast feeding their babies.
It is noteworthy that these medical specialty groups have received significant funding from Pfizer pharmaceutical company. The American College of Obstetrics and Gynecology, just in the 4th quarter of 2010, received a total of $11,000 from Pfizer Pharmaceutical company alone. Funding from NIH grants are much higher. The best way to lose these grants is to criticize the source of the funds, their products or pet programs. Peter Duesberg, because of his daring to question Fauci’s pet theory of AIDS caused by HIV virus, was no longer awarded any of the 30 grant applications he submitted after going public. Prior to this episode, as the leading authority on retroviruses in the world, he had never been turned down for an NIH grant. This is how the “corrupted” system works, even though much of the grant money comes from our taxes.
HOT LOTS—DEADLY BATCHES OF THE VACCINES
A new study has now surfaced, the results of which are terrifying. A researcher at Kingston University in London, has completed an extensive analysis of the VAERs data (a subdepartment of the CDC which collects voluntary vaccine complication data), in which he grouped reported deaths following the vaccines according to the manufacturer’s lot numbers of the vaccines. Vaccines are manufactured in large batches called lots. What he discovered was that the vaccines are divided into over 20,000 lots and that one out of every 200 of these batches (lots) is demonstrably deadly to anyone who receives a vaccine from that lot, which includes thousands of vaccine doses.
He examined all manufactured vaccines—Pfizer, Moderna, Johnson and Johnson (Janssen), etc. He found that among every 200 batches of the vaccine from Pfizer and other makers, one batch of the 200 was found to be over 50x more deadly than vaccines batches from other lots. The other vaccine lots (batches) were also causing deaths and disabilities, but nowhere near to this extent. These deadly batches should have appeared randomly among all “vaccines” if it was an unintentional event. However, he found that 5% of the vaccines were responsible for 90% of the serious adverse events, including deaths. The incidence of deaths and serious complications among these “hot lots” varied from over 1000% to several thousand percent higher than comparable safer lots. If you think this was by accident—think again. This is not the first time “hot lots” were, in my opinion, purposefully manufactured and sent across the nation—usually vaccines designed for children. In one such scandal, “hot lots” of a vaccine ended up all in one state and the damage immediately became evident. What was the manufacture’s response? It wasn’t to remove the deadly batches of the vaccine. He ordered his company to scatter the hot lots across the nation so that authorities would not see the obvious deadly effect.
All lots of a vaccine are numbered—for example Modera labels them with such codes as 013M20A. It was noted that the batch numbers ended in either 20A or 21A. Batches ending in 20A were much more toxic than the ones ending in 21A. The batches ending in 20A had about 1700 adverse events, versus a few hundred to twenty or thirty events for the 21A batches. This example explains why some people had few or no adverse events after taking the vaccine while others are either killed or severely and permanently harmed. To see the researcher’s explanation, go to https://www.bitchute.com/video/6xIYPZBkydsu/ In my opinion these examples strongly suggest an intentional alteration of the production of the “vaccine” to include deadly batches.
I have met and worked with a number of people concerned with vaccine safety and I can tell you they are not the evil anti-vaxxers you are told they are. They are highly principled, moral, compassionate people, many of which are top researchers and people who have studied the issue extensively. Robert Kennedy, Jr, Barbara Lou Fisher, Dr. Meryl Nass, Professor Christopher Shaw, Megan Redshaw, Dr. Sherri Tenpenny, Dr. Joseph Mercola, Neil Z. Miller, Dr. Lucija Tomjinovic, Dr. Stephanie Seneff, Dr. Steve Kirsch and Dr. Peter McCullough just to name a few. These people have nothing to gain and a lot to lose. They are attacked viciously by the media, government agencies, and elite billionaires who think they should control the world and everyone in it.
WHY DID FAUCI WANT NO AUTOPSIES OF THOSE WHO DIED AFTER VACCINATION?
There are many things about this “pandemic” that are unprecedented in medical history. One of the most startling is that at the height of the pandemic so few autopsies, especially total autopsies, were being done. A mysterious virus was rapidly spreading around the world, a selected group of people with weakened immune systems were getting seriously ill and many were dying and the one way we could rapidly gain the most knowledge about this virus—an autopsy, was being discouraged.
Guerriero noted that by the end of April, 2020 approximately 150,000 people had died, yet there were only 16 autopsies performed and reported in the medical literature. Among these, only seven were complete autopsies, the remaining 9 being partial or by needle biopsy or incisional biopsy. Only after 170,000 deaths by Covid-19 and four months into the pandemic were the first series of autopsies actually done, that is, more than ten. And only after 280,000 deaths and another month, were the first large series of autopsies performed, some 80 in number. Sperhake, in a call for autopsies to be done without question, noted that the first full autopsy reported in the literature along with photomicrographs appeared in a medico-legal journal from China in February 2020.[41,68] Sperhake expressed confusion as to why there was a reluctance to perform autopsies during the crisis, but he knew it was not coming from the pathologists. The medical literature was littered with appeals by pathologist for more autopsies to be performed. Sperhake further noted that the Robert Koch Institute (The German health monitoring system) at least initially advised against doing autopsies. He also knew that at the time 200 participating autopsy institutions in the United States had done at least 225 autopsies among 14 states.
Some have claimed that this dearth of autopsies was based on the government’s fear of infection among the pathologists, but a study of 225 autopsies on Covid-19 cases demonstrated only one case of infection among the pathologist and this was concluded to have been an infection contracted elsewhere. Guerriero ends his article calling for more autopsies with this observation: “Shoulder to shoulder, clinical and forensic pathologists overcame the obstructions of autopsy studies in Covid-19 victims and hereby generated valuable knowledge on the pathophysiology of the interaction between the SARS-CoV-2 and the human body, thus contributing to our understanding of the disease.”
Suspicion concerning the worldwide reluctance of nations to allow full post mortem studies of Covid-19 victims may be based on the idea that it was more than by chance. There are at least two possibilities that stand out. First, those leading the progression of this “non-pandemic” event into a perceived worldwide “deadly pandemic”, were hiding an important secret that autopsies could document. Namely, just how many of the deaths were actually caused by the virus? To implement draconian measures, such as mandated mask wearing, lockdowns, destruction of businesses, and eventually mandated forced vaccination, they needed very large numbers of covid-19 infected dead. Fear would be the driving force for all these destructive pandemic control programs.
Elder et al in his study classified the autopsy findings into four groups.
Certain Covid-19 death
Probably Covid-19 death
Possible Covid-19 death
Not associated with Covid-19, despite the positive test.
What possibly concerned or even terrified the engineers of this pandemic was that autopsies just might, and did, show that a number of these so-called Covid-19 deaths in truth died of their comorbid diseases. In the vast majority of autopsy studies reported, pathologists noted multiple comorbid conditions, most of which at the extremes of life could alone be fatal. Previously it was known that common cold viruses had an 8% mortality in nursing homes.
In addition, valuable evidence could be obtained from the autopsies that would improve clinical treatments and could possibly demonstrate the deadly effect of the CDC mandated protocols all hospitals were required to follow, such as the use of respirators and the deadly, kidney-destroying drug remdesivir. The autopsies also demonstrated accumulating medical errors and poor-quality care, as the shielding of doctors in intensive care units from the eyes of family members inevitably leads to poorer quality care as reported by several nurses working in these areas.[53–55]
As bad as all this was, the very same thing is being done in the case of Covid vaccine deaths—very few complete autopsies have been done to understand why these people died, that is, until recently. Two highly qualified researchers, Dr. Sucharit Bhakdi a microbiologist and highly qualified expert in infectious disease and Dr. Arne Burkhardt, a pathologist who is a widely published authority having been a professor of pathology at several prestigious institutions, recently performed autopsies on 15 people having died after vaccination. What they found explains why so many are dying and experiencing organ damage and deadly blood clots.
They determined that 14 of the fifteen people died as a result of the vaccines and not of other causes. Dr. Burkhardt, the pathologist, observed widespread evidence of an immune attack on the autopsied individuals’ organs and tissues— especially their heart. This evidence included extensive invasion of small blood vessels with massive numbers of lymphocytes, which cause extensive cell destruction when unleashed. Other organs, such as the lungs and liver, were observed to have extensive damage as well. These findings indicate the vaccines were causing the body to attack itself with deadly consequences. One can easily see why Anthony Fauci, as well as public health officers and all who are heavily promoting these vaccines, publicly discouraged autopsies on the vaccinated who subsequently died. One can also see that in the case of vaccines, that were essentially untested prior to being approved for the general public, at least the regulatory agencies should have been required to carefully monitor and analyze all serious complications, and certainly deaths, linked to these vaccines. The best way to do that is with complete autopsies.
While we learned important information from these autopsies what is really needed are special studies of the tissues of those who have died after vaccination for the presence of spike protein infiltration throughout the organs and tissues. This would be critical information, as such infiltration would result in severe damage to all tissues and organs involved—especially the heart, the brain, and the immune system. Animal studies have demonstrated this. In these vaccinated individuals the source of these spike proteins would be the injected nanolipid carriers of the spike protein producing mRNA. It is obvious that the government health authorities and pharmaceutical manufacturers of these “vaccines” do not want these critical studies done as the public would be outraged and demand an end to the vaccination program and prosecution of the involved individuals who covered this up.
We are all living through one of the most drastic changes in our culture, economic system, as well as political system in our nation’s history as well as the rest of the world. We have been told that we will never return to “normal” and that a great reset has been designed to create a “new world order”. This has all been outlined by Klaus Schwab, head of the World Economic Forum, in his book on the “Great Reset”. This book gives a great deal of insight as to the thinking of the utopians who are proud to claim this pandemic “crisis” as their way to usher in a new world. This new world order has been on the drawing boards of the elite manipulators for over a century.[73,74] In this paper I have concentrated on the devastating effects this has had on the medical care system in the United States, but also includes much of the Western world. In past papers I have discussed the slow erosion of traditional medical care in the United States and how this system has become increasingly bureaucratized and regimented.[7,8] This process was rapidly accelerating, but the appearance of this, in my opinion, manufactured “pandemic” has transformed our health care system over night.
As you have seen, an unprecedented series of events have taken place within this system. Hospital administrators, for example, assumed the position of medical dictators, ordering doctors to follow protocols derived not from those having extensive experience in treating this virus, but rather from a medical bureaucracy that has never treated a single COVID-19 patient. The mandated use of respirators on ICU Covid-19 patients, for example, was imposed in all medical systems and dissenting physicians were rapidly removed from their positions as caregivers, despite their demonstration of markedly improved treatment methods. Further, doctors were told to use the drug remdesivir despite its proven toxicity, lack of effectiveness and high complication rate. They were told to use drugs that impaired respiration and mask every patient, despite the patient’s impaired breathing. In each case, those who refused to abuse their patients were removed from the hospital and even faced a loss of license—or worse.
For the first time in modern medical history, early medical treatment of these infected patients was ignored nationwide. Studies have shown that early medical treatment was saving 80% of higher number of these infected people when initiated by independent doctors.[43,44] Early treatment could have saved over 640,000 lives over the course of this “pandemic”. Despite the demonstration of the power of these early treatments, the forces controlling medical care continued this destructive policy.
Families were not allowed to see their loved ones, forcing these very sick individuals in the hospitals to face their deaths alone. To add insult to injury, funerals were limited to a few grieving family members, who were not allowed to even sit together. All the while large stores, such as Walmart and Cosco were allowed to operate with minimal restrictions. Nursing home patients were also not allowed to have family visitations, again being forced to die a lonely death. All the while, in a number of states, the most transparent being in New York state, infected elderly were purposefully transferred from hospitals into nursing homes, resulting in a very high death rates of these nursing home residents. At the beginning of this “pandemic” over 50% of all death were occurring in nursing homes.
Throughout this “pandemic” we have been fed an unending series of lies, distortions and disinformation by the media, the public health officials, medical bureaucracies (CDC, FDA and WHO) and medical associations. Physicians, scientists, and experts in infectious treatments who formed associations designed to develop more effective and safer treatments, were regularly demonized, harassed, shamed, humiliated, and experience a loss of licensure, loss of hospital privileges and, in at least one case, ordered to have a psychiatric examination.[2,65,71]
Anthony Fauci was given essentially absolute control of all forms of medical care during this event, including insisting that drugs he profited from be used by all treating physicians. He ordered the use of masks, despite at first laughing at the use of masks to filter a virus. Governors, mayors, and many businesses followed his orders without question.
The draconian measures being used, masking, lockdowns, testing of the uninfected, use of the inaccurate PCR test, social distancing, and contact tracing had been shown previously to be of little or no use during previous pandemics, yet all attempts to reject these methods were to no avail. Some states ignored these draconian orders and had either the same or fewer cases, as well as deaths, as the states with the most strictly enforced measures. Again, no amount of evidence or obvious demonstration along these lines had any effect on ending these socially destructive measures. Even when entire countries, such as Sweden, which avoided all these measures, demonstrated equal rates of infections and hospitalization as nations with the strictest, very draconian measures, no policy change by the controlling institutions occurred. No amount of evidence changed anything.
Experts in the psychology of destructive events, such as economic collapses, major disasters and previous pandemics demonstrated that draconian measures come with an enormous cost in the form of “deaths of despair” and in a dramatic increase in serious psychological disorders. The effects of these pandemic measures on children’s neurodevelopment is catastrophic and to a large extent irreversible.
Over time tens of thousands could die as a result of this damage. Even when these predictions began to appear, the controllers of this “pandemic” continued full steam ahead. Drastic increases in suicides, a rise in obesity, a rise in drug and alcohol use, a worsening of many health measures and a terrifying rise in psychiatric disorders, especially depression and anxiety, were ignored by the officials controlling this event.
We eventually learned that many of the deaths were a result of medical neglect. Individuals with chronic medical conditions, diabetes, cancer, cardiovascular disease, and neurological diseases were no longer being followed properly in their clinics and doctor’s offices. Non-emergency surgeries were put on hold. Many of these patients chose to die at home rather than risk going to the hospitals and many considered hospitals “death houses”.
Records of deaths have shown that there was a rise in deaths among those aged 75 and older, mostly explained by Covid-19 infections, but for those between the ages of 65 to 74, deaths had been increasing well before the pandemic onset. Between ages of 18 and aged 65 years, records demonstrate a shocking hike in non-Covid-19 deaths. Some of these deaths were explained by a dramatic increase in drug-related deaths, some 20,000 more than 2019. Alcohol related deaths also increased substantially, and homicides increased almost 30% in the 18 to 65-year group.
The head of the insurance company OneAmerica stated that their data indicated that the death rate for individuals aged 18 to 64 had increased 40% over the pre-pandemic period. Scott Davidson, the company’s CEO, stated that this represented the highest death rate in the history of insurance records, which does extensive data collections on death rates each year. Davidson also noted that this high of a death rate increase has never been seen in the history of death data collection. Previous catastrophes of monumental extent increased death rates no more than 10 percent, 40% is unprecedented.
Dr. Lindsay Weaver, Indiana’s chief medical officer, stated that hospitalizations in Indiana are higher than at any point in the past five years. This is of critical importance since the vaccines were supposed to significantly reduce deaths, but the opposite has happened. Hospitals are being flooded with vaccine complications and people in critical condition from medical neglect caused by the lockdowns and other pandemic measures.[46,56]
A dramatic number of these people are now dying, with the spike occurring after the vaccines were introduced. The lies flowing from those who have appointed themselves as medical dictators are endless. First, we were told that the lockdown would last only two weeks, they lasted over a year. Then we were told that masks were ineffective and did not need to be worn. Quickly that was reversed. Then we were told the cloth mask was very effective, now it’s not and everyone should be wearing an N95 mask and before that that they should double mask. We were told there was a severe shortage of respirators, then we discover they are sitting unused in warehouses and in city dumps, still in their packing crates. We were informed that the hospitals were filled mostly with the unvaccinated and later found the exact opposite was true the world over. We were told that the vaccine was 95% effective, only to learn that in fact the vaccines cause a progressive erosion of innate immunity.
Upon release of the vaccines, women were told the vaccines were safe during all states of pregnancy, only to find out no studies had been done on safety during pregnancy during the “safety tests” prior to release of the vaccine. We were told that careful testing on volunteers before the EUA approval for public use demonstrated extreme safety of the vaccines, only to learn that these unfortunate subjects were not followed, medical complications caused by the vaccines were not paid for and the media covered this all up. We also learned that the pharmaceutical makers of the vaccines were told by the FDA that further animal testing was unnecessary (the general public would be the Guinea pigs.) Incredibly, we were told that the Pfizer’s new mRNA vaccines had been approved by the FDA, which was a cleaver deception, in that another vaccine had approval (comirnaty) and not the one being used, the BioNTech vaccine. The approved comirnaty vaccine was not available in the United States. The national media told the public that the Pfizer vaccine had been approved and was no longer classed as experimental, a blatant lie. These deadly lies continue. It is time to stop this insanity and bring these people to justice.
How to cite this article: Blaylock RL. COVID UPDATE: What is the truth? Surg Neurol Int 2022;13:167.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
Articles from Surgical Neurology International are provided here courtesy of Scientific Scholar
11. Bosh X, Ross JS. Ghostwriting: Research misconduct, plagiarism, or Fool’s gold. Amer J Med. 2012;125(4):324–6. [PubMed] [Google Scholar]
12. Breggin PR, Breggin GR. Breggin PR, Breggin GR. Covid-19 and the Global Predators: We are the Prey. Ithaca, NY: Lake Edge Press; 2021. Top Medical Journals Sell their Souls; pp. 285–292. [Google Scholar]
15. Children’s Health Defense Team Harvard experts critique cozy FDA-Pharma relationship. The Defender. Jan 28, 29020.
16. Chughtai AA, Stelzer-Braid S, Rawlinson W, Pontivivi G, Wang Q, Pan Y, et al. Contamination by respiratory viruses on outer surface of medical mask used by hospital healthcare workers. BMC Infect Dis. 2019. Article number 491.
21. Durden T. Life Insurance CEO says deaths up 40% among those aged 18 to 64. Tyler Durden Report. 2022. Jan 3,
22. Elder C, Schroder AS, Aepfelbacher M, Fitzek A, Heinemann A, Heinrich F, et al. Dying with SARS-CoV-2 infection an autopsy study of the first consecutive 80 cases in Hamberg, Germany. Inter J Legal Med. 2020;134:1275–84. [Google Scholar]
27. Ioannou P, Karakonstantis S, Astrinaki E, Saplamidou S, Vitsaxaki E, Hamilos G, et al. Transmission of SARS-C0V-2 variant B1.1.7 among vaccinated health care workers. Infect Dis. 2021:1–4. [Google Scholar]
61. Redshaw M. As reports of injuries after Covid vaccines near 1 million mark. CDC, FDA clear Pfizer, Moderna boosters for all adults. The Defender 11/19/21.
62. Roche D. Boston Herald. 2021. Sept 14, Members of Congress and their staff are exempt from Biden’s vaccine mandate, Newsweek 9/10/21 Boston Herald Editorial Staff. Editorial: Political elites exempt from vax mandates. [Google Scholar]
Our enemies are obsessed with jamming our OODA Loops. They do not want us to have even a moment to think. An OODA loop is a decision making process: observe–orient–decide–act. We take in information, and we make a decision on how to act to change things. Our enemies keep distracting us with constantly changing information, and we keep getting stuck in the OO stage, never making decisions, never acting to change things, because we are constantly trying to figure out the nature of the trap we are caught in. But that is the trap we are caught in! We end up stuck in endless puzzling debates, making no productive plans to achieve victory in even one small way.
When a fresh news story gets hyped up, and people say “oh oh they are just distracting us”, it is THINKING TIME they are distracting us from. A moment for the dust to settle, for even a minute of propaganda-free time, to be able to make a plan to counter our enemy’s plans. They cannot allow us this minute. We are allowed no firm place to stand. They have to bombard us with useless factoids and storylines 24/7, little rabbit holes and dead-ends and intrigue and drama, or else we might form together into something capable of defeating their psychological operations. Distraction and overload is their primary weapon against us. Unfortunately, we keep falling for this trick.
The OODA loop is the cycle observe–orient–decide–act, developed by military strategist and United States Air Force Colonel John Boyd. Boyd applied the concept to the combat operations process, often at the operational level during military campaigns. It is now also often applied to understand commercial operations and learning processes. The approach explains how agility can overcome raw power in dealing with human opponents. It is especially applicable to cyber security and cyberwarfare.
The OODA loop has become an important concept in litigation, business,law enforcement, and military strategy. According to Boyd, decision-making occurs in a recurring cycle of observe–orient–decide–act. An entity (whether an individual or an organization) that can process this cycle quickly, observing and reacting to unfolding events more rapidly than an opponent, can thereby “get inside” the opponent’s decision cycle and gain the advantage.
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
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.
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 . In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [, , , ] (Fig. 1 ). IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 . 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 , schistosomiasis , trichinosis  and leishmaniasis .
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 ; 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 . 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 . In addition, IVM shows potential for clinical application in asthma  and neurological diseases . 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 , a few relevant studies have emphasized the potential use of IVM as a new cancer
treatment [, , , , ]. 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 . 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 . 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 . 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 .
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.
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) . 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 . 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). 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 .
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 . 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 . IVM could inhibit the development of hepatocellular carcinoma by blocking YAP1 activity in spontaneous liver cancer Mob1b-/-mice .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 . 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 [, , ]. 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 . 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 . 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 . Interestingly, IVM also restored the sensitivity of the triple-negative breast cancer to the anti-estrogen drug tamoxifen , 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 .
2.4. Hematological cancer
Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells . 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 . 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 . 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 . 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 . 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 . 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 .
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 . 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 .
In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion . The DDX23 helicase activity affects the expression of miR-12 . 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 , 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 . 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 . 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 . Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity . 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 . In addition, IVM could reduce the metastasis of lung cancer cells by inhibiting EMT.
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 . 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 . 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
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 .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.
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 . 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 [, , , ]. 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 . 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 . 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 . 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 . 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 . 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.
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 . 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 . 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 [, , ]. 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 . 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 .
4.2. Reversal of tumor multidrug resistance
MDR of tumor cells is the main cause of relapses and deaths after chemotherapy . 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 [, , ]. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [, , ]. 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 . 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 . 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  and gemcitabine-resistant cholangiocarcinoma . 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 . 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 . Earlier, we mentioned that IVM combined with conventional chemotherapeutic drugs such as cisplatin , paclitaxel , daunorubicin and cytarabine , or with targeted drugs such as dasatinib  and dapafenib  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 . 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 . 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 .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  In addition, IVM has also been proven to show good permeability in tumor tissues . 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  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.
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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This article has been cited by other articles in PMC.
1. Campbell W.C., Fisher M.H., Stapley E.O., Albers-Schonberg G., Jacob T.A. Ivermectin: a potent new antiparasitic agent. Science. 1983;221(4613):823–828. doi: 10.1126/science.6308762. [PubMed] [CrossRef] [Google Scholar]
2. Prichard R.K., Geary T.G. Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. Int J Parasitol Drugs Drug Resist. 2019;10:69–83. doi: 10.1016/j.ijpddr.2019.06.002.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
3. Ashour D.S. Ivermectin: From theory to clinical application. Int J Antimicrob Agents. 2019;54(2):134–142. doi: 10.1016/j.ijantimicag.2019.05.003.[PubMed] [CrossRef] [Google Scholar]
7. Crump A. Ivermectin: enigmatic multifaceted’ wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo) 2017;70(5):495–505. doi: 10.1038/ja.2017.11. [PubMed] [CrossRef] [Google Scholar]
8. McKerrow J.H. Recognition of the role of Natural Products as drugs to treat neglected tropical diseases by the 2015 Nobel prize in physiology or medicine. Nat Prod Rep. 2015;32(12):1610–1611. doi: 10.1039/c5np90043c. [PubMed] [CrossRef] [Google Scholar]
9. 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. Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proc Natl Acad Sci U S A. 2000;97(25):13949–13954. doi: 10.1073/pnas.240464697.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
10. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Proc Natl Acad Sci U S A. 1979;76(4):2062–2066. doi: 10.1073/pnas.76.4.2062. [PMC free article][PubMed] [CrossRef] [Google Scholar]
11. Smit M.R., Ochomo E.O., Aljayyoussi G., Kwambai T.K., Abong’o B.O., Chen T., Bousema T., Slater H.C., Waterhouse D., Bayoh N.M., Gimnig J.E., Samuels A.M., Desai M.R., Phillips-Howard P.A., Kariuki S.K., Wang D., Ward S.A., Ter Kuile F.O. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(6):615–626. doi: 10.1016/s1473-3099(18)30163-4. [PubMed] [CrossRef] [Google Scholar]
12. Foy B.D., Alout H., Seaman J.A., Rao S., Magalhaes T., Wade M., Parikh S., Soma D.D., Sagna A.B., Fournet F., Slater H.C., Bougma R., Drabo F., Diabate A., Coulidiaty A.G.V., Rouamba N., Dabire R.K. Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial. Lancet. 2019;393(10180):1517–1526. doi: 10.1016/s0140-6736(18)32321-3.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
13. Udensi U.K., Fagbenro-Beyioku A.F. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. J Vector Borne Dis. 2012;49(3):143–150.[PubMed] [Google Scholar]
14. Katz N., Araujo N., Coelho P.M.Z., Morel C.M., Linde-Arias A.R., Yamada T., Horimatsu Y., Suzuki K., Sunazuka T., Omura S. Ivermectin efficacy against Biomphalaria, intermediate host snail vectors of Schistosomiasis. J Antibiot (Tokyo) 2017;70(5):680–684. doi: 10.1038/ja.2017.31.[PubMed] [CrossRef] [Google Scholar]
15. B. MM, E.-S. AA Therapeutic potential of myrrh and ivermectin against experimental Trichinella spiralis infection in mice. The Korean journal of parasitology. 2013;51(3):297–304. doi: 10.3347/kjp.2013.51.3.297.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
16. Hanafi H.A., Szumlas D.E., Fryauff D.J., El-Hossary S.S., Singer G.A., Osman S.G., Watany N., Furman B.D., Hoel D.F. Effects of ivermectin on blood-feeding Phlebotomus papatasi, and the promastigote stage of Leishmania major. Vector Borne Zoonotic Dis. 2011;11(1):43–52. doi: 10.1089/vbz.2009.0030. [PubMed] [CrossRef] [Google Scholar]
17. Mastrangelo E., Pezzullo M., De Burghgraeve T., Kaptein S., Pastorino B., Dallmeier K., de Lamballerie X., Neyts J., Hanson A.M., Frick D.N., Bolognesi M., Milani M. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012;67(8):1884–1894. doi: 10.1093/jac/dks147. [PMC free article][PubMed] [CrossRef] [Google Scholar]
18. Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851–856. doi: 10.1042/bj20120150. [PMC free article][PubMed] [CrossRef] [Google Scholar]
19. Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020:104787. doi: 10.1016/j.antiviral.2020.104787.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Yan S., Ci X., Chen N., Chen C., Li X., Chu X., Li J., Deng X. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res. 2011;60(6):589–596. doi: 10.1007/s00011-011-0307-8.[PubMed] [CrossRef] [Google Scholar]
21. Franklin K.M., Asatryan L., Jakowec M.W., Trudell J.R., Bell R.L., Davies D.L. P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders. Front Neurosci. 2014;8:176. doi: 10.3389/fnins.2014.00176.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. Anticancer Drugs. 1996;7(7):745–751. doi: 10.1097/00001813-199609000-00005. [PubMed] [CrossRef] [Google Scholar]
23. Markowska A., Kaysiewicz J., Markowska J., Huczynski A. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. Bioorg Med Chem Lett. 2019;29(13):1549–1554. doi: 10.1016/j.bmcl.2019.04.045. [PubMed] [CrossRef] [Google Scholar]
24. Juarez M., Schcolnik-Cabrera A., Duenas-Gonzalez A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018;8(2):317–331. [PMC free article][PubMed] [Google Scholar]
25. Liu J., Zhang K., Cheng L., Zhu H., Xu T. Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin. Drug Des Devel Ther. 2020;14:285–296. doi: 10.2147/dddt.S237393.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
26. Antoszczak M., Markowska A., Markowska J., Huczynski A. Old wine in new bottles: Drug repurposing in oncology. Eur J Pharmacol. 2020;866:172784. doi: 10.1016/j.ejphar.2019.172784. [PubMed] [CrossRef] [Google Scholar]
27. Kobayashi Y., Banno K., Kunitomi H., Tominaga E., Aoki D. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. J Gynecol Oncol. 2019;30(1):e10. doi: 10.3802/jgo.2019.30.e10.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
28. Yoshida G.J. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10(1):67. doi: 10.1186/s13045-017-0436-9.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
29. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. Drug Discov Today. 2016;21(1):190–199. doi: 10.1016/j.drudis.2015.09.017. [PubMed] [CrossRef] [Google Scholar]
30. Harbeck N., Penault-Llorca F., Cortes J., Gnant M., Houssami N., Poortmans P., Ruddy K., Tsang J., Cardoso F. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66. doi: 10.1038/s41572-019-0111-2. [PubMed] [CrossRef] [Google Scholar]
31. Ginsburg O., Bray F., Coleman M.P., Vanderpuye V., Eniu A., Kotha S.R., Sarker M., Huong T.T., Allemani C., Dvaladze A., Gralow J., Yeates K., Taylor C., Oomman N., Krishnan S., Sullivan R., Kombe D., Blas M.M., Parham G., Kassami N., Conteh L. The global burden of women’s cancers: a grand challenge in global health. Lancet. 2017;389(10071):847–860. doi: 10.1016/s0140-6736(16)31392-7.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
32. Dou Q., Chen H.N., Wang K., Yuan K., Lei Y., Li K., Lan J., Chen Y., Huang Z., Xie N., Zhang L., Xiang R., Nice E.C., Wei Y., Huang C. Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer. Cancer Res. 2016;76(15):4457–4469. doi: 10.1158/0008-5472.CAN-15-2887.[PubMed] [CrossRef] [Google Scholar]
33. 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. BMC Vet Res. 2019;15(1):276. doi: 10.1186/s12917-019-2026-2.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. 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. Cancers (Basel) 2020;12(4) doi: 10.3390/cancers12040819.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. Deepak K.G.K., Vempati R., Nagaraju G.P., Dasari V.R., N. S, Rao D.N., Malla R.R. Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol Res. 2020;153:104683. doi: 10.1016/j.phrs.2020.104683. [PubMed] [CrossRef] [Google Scholar]
36. Kwon Y.J., Petrie K., Leibovitch B.A., Zeng L., Mezei M., Howell L., Gil V., Christova R., Bansal N., Yang S., Sharma R., Ariztia E.V., Frankum J., Brough R., Sbirkov Y., Ashworth A., Lord C.J., Zelent A., Farias E., Zhou M.M., Waxman S. Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. Mol Cancer Ther. 2015;14(8):1824–1836. doi: 10.1158/1535-7163.MCT-14-0980-T.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Draganov D., Gopalakrishna-Pillai S., Chen Y.R., Zuckerman N., Moeller S., Wang C., Ann D., Lee P.P. Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci Rep. 2015;5:16222. doi: 10.1038/srep16222. [PMC free article][PubMed] [CrossRef] [Google Scholar]
38. Thanh Huong P., Gurshaney S., Thanh Binh N., Gia Pham A., Hoang Nguyen H., Thanh Nguyen X., Pham-The H., Tran P.T., Truong Vu K., Xuan Duong N., Pelucchi C., La Vecchia C., Boffetta P., Nguyen H.D., Luu H.N. Emerging Role of Circulating Tumor Cells in Gastric Cancer. Cancers (Basel) 2020;12(3) doi: 10.3390/cancers12030695.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
39. Nambara S., Masuda T., Nishio M., Kuramitsu S., Tobo T., Ogawa Y., Hu Q., Iguchi T., Kuroda Y., Ito S., Eguchi H., Sugimachi K., Saeki H., Oki E., Maehara Y., Suzuki A., Mimori K. Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer. Oncotarget. 2017;8(64):107666–107677. doi: 10.18632/oncotarget.22587.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Zanconato F., Cordenonsi M., Piccolo S. YAP and TAZ: a signalling hub of the tumour microenvironment. Nat Rev Cancer. 2019;19(8):454–464. doi: 10.1038/s41568-019-0168-y. [PubMed] [CrossRef] [Google Scholar]
41. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med. 2014;6(10):1263–1278. doi: 10.15252/emmm.201404084.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
42. Yang J.D., Hainaut P., Gores G.J., Amadou A., Plymoth A., Roberts L.R. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604. doi: 10.1038/s41575-019-0186-y.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
43. 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. Proc Natl Acad Sci U S A. 2016;113(1):71–80. doi: 10.1073/pnas.1517188113.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Intuyod K., Hahnvajanawong C., Pinlaor P., Pinlaor S. Anti-parasitic Drug Ivermectin Exhibits Potent Anticancer Activity Against Gemcitabine-resistant Cholangiocarcinoma In Vitro. Anticancer Res. 2019;39(9):4837–4843. doi: 10.21873/anticanres.13669. [PubMed] [CrossRef] [Google Scholar]
45. Wang Y., Su J., Wang Y., Fu D., Ideozu J.E., Geng H., Cui Q., Wang C., Chen R., Yu Y., Niu Y., Yue D. The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1-SPP1- NF-kappaB signaling axis. J Exp Clin Cancer Res. 2019;38(1):386. doi: 10.1186/s13046-019-1347-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
46. Xu W.H., Shi S.N., Xu Y., Wang J., Wang H.K., Cao D.L., Shi G.H., Qu Y.Y., Zhang H.L., Ye D.W. Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma. J Transl Med. 2019;17(1):363. doi: 10.1186/s12967-019-2113-y.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
47. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. doi: 10.3322/caac.21551.[PubMed] [CrossRef] [Google Scholar]
48. Zhu M., Li Y., Zhou Z. Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. Biochemical and Biophysical Research Communications. 2017;492(3):373–378. doi: 10.1016/j.bbrc.2017.08.097. [PubMed] [CrossRef] [Google Scholar]
50. 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. J Clin Invest. 2020;130(2):699–714. doi: 10.1172/jci130819.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
51. Sharmeen S., Skrtic M., Sukhai M.A., Hurren R., Gronda M., Wang X., Fonseca S.B., Sun H., Wood T.E., Ward R., Minden M.D., Batey R.A., Datti A., Wrana J., Kelley S.O., Schimmer A.D. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010;116(18):3593–3603. doi: 10.1182/blood-2010-01-262675.[PubMed] [CrossRef] [Google Scholar]
53. Wang J., Xu Y., Wan H., Hu J. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2018;497(1):241–247. doi: 10.1016/j.bbrc.2018.02.063. [PubMed] [CrossRef] [Google Scholar]
54. 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. Artif Cells Nanomed Biotechnol. 2019;47(1):3711–3719. doi: 10.1080/21691401.2019.1664560.[PubMed] [CrossRef] [Google Scholar]
55. Carneiro S.R., da Silva Lima A.A., de Fatima Silva Santos G., de Oliveira C.S.B., Almeida M.C.V., da Conceicao Nascimento Pinheiro M. Relationship between Oxidative Stress and Physical Activity in Women with Squamous Intraepithelial Lesions in a Cervical Cancer Control Program in the Brazilian Amazon. Oxid Med Cell Longev. 2019;2019doi: 10.1155/2019/8909852. [PMC free article][PubMed] [CrossRef] [Google Scholar]
56. 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. Cell Prolif. 2019;52(2):e12543. doi: 10.1111/cpr.12543.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
57. Moufarrij S., Dandapani M., Arthofer E., Gomez S., Srivastava A., Lopez-Acevedo M., Villagra A., Chiappinelli K.B. Epigenetic therapy for ovarian cancer: promise and progress. Clin Epigenetics. 2019;11(1):7. doi: 10.1186/s13148-018-0602-0.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Hashimoto H., Messerli S.M., Sudo T., Maruta H. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009;3(6):243–246.[PubMed] [Google Scholar]
59. 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. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2017;114(35):E7301–E7310. doi: 10.1073/pnas.1705441114.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
60. 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. Am J Med Sci. 2020;359(2):123–129. doi: 10.1016/j.amjms.2019.11.001. [PubMed] [CrossRef] [Google Scholar]
61. Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15(7):405–417. doi: 10.1038/s41582-019-0220-2.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Wen P.Y., Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507. doi: 10.1056/NEJMra0708126. [PubMed] [CrossRef] [Google Scholar]
63. Liu Y., Fang S., Sun Q., Liu B. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2016;480(3):415–421. doi: 10.1016/j.bbrc.2016.10.064. [PubMed] [CrossRef] [Google Scholar]
64. Liu J., Liang H., Chen C., Wang X., Qu F., Wang H., Yang K., Wang Q., Zhao N., Meng J., Gao A. Ivermectin induces autophagy-mediated cell death through the AKT/mTOR signaling pathway in glioma cells. Biosci Rep. 2019;39(12) doi: 10.1042/bsr20192489.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
65. 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. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene. 2011;30(21):2433–2442. doi: 10.1038/onc.2010.620. [PubMed] [CrossRef] [Google Scholar]
66. Yin J., Park G., Lee J.E., Choi E.Y., Park J.Y., Kim T.H., Park N., Jin X., Jung J.E., Shin D., Hong J.H., Kim H., Yoo H., Lee S.H., Kim Y.J., Park J.B., Kim J.H. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain. 2015;138(Pt 9):2553–2570. doi: 10.1093/brain/awv167. [PubMed] [CrossRef] [Google Scholar]
67. Kircik L.H., Del Rosso J.Q., Layton A.M., Schauber J. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. J Drugs Dermatol. 2016;15(3):325–332. [PubMed] [Google Scholar]
68. Chen Y.P., Chan A.T.C., Le Q.T., Blanchard P., Sun Y., Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64–80. doi: 10.1016/s0140-6736(19)30956-0.[PubMed] [CrossRef] [Google Scholar]
69. Gallardo F., Mariamé B., Gence R., Tilkin-Mariamé A.-F. Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth. Drug Design, Development and Therapy. 2018;12:2805–2814. doi: 10.2147/dddt.S172538. [PMC free article][PubMed] [CrossRef] [Google Scholar]
70. Thawani R., McLane M., Beig N., Ghose S., Prasanna P., Velcheti V., Madabhushi A. Radiomics and radiogenomics in lung cancer: A review for the clinician. Lung Cancer. 2018;115:34–41. doi: 10.1016/j.lungcan.2017.10.015. [PubMed] [CrossRef] [Google Scholar]
71. Patel H., Yacoub N., Mishra R., White A., Long Y., Alanazi S., Garrett J.T. Current Advances in the Treatment of BRAF-Mutant Melanoma. Cancers (Basel) 2020;12(2) doi: 10.3390/cancers12020482.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
72. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma. Eur J Cancer. 2019;123:58–71. doi: 10.1016/j.ejca.2019.08.032. [PubMed] [CrossRef] [Google Scholar]
73. Gallardo F., Teiti I., Rochaix P., Demilly E., Jullien D., Mariamé B., Tilkin-Mariamé A.-F. Macrocyclic Lactones Block Melanoma Growth, Metastases Development and Potentiate Activity of Anti– BRAF V600 Inhibitors. Clinical Skin Cancer. 2016;1(1):4–14. doi: 10.1016/j.clsc.2016.05.001. e3. [CrossRef] [Google Scholar]
74. Deng F., Xu Q., Long J., Xie H. Suppressing ROS‐TFE3‐dependent autophagy enhances ivermectin‐induced apoptosis in human melanoma cells. Journal of Cellular Biochemistry. 2018;120(2):1702–1715. doi: 10.1002/jcb.27490. [PubMed] [CrossRef] [Google Scholar]
75. Nagata S. Apoptosis and Clearance of Apoptotic Cells. Annu Rev Immunol. 2018;36:489–517. doi: 10.1146/annurev-immunol-042617-053010. [PubMed] [CrossRef] [Google Scholar]
76. Degterev A., Yuan J. Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol. 2008;9(5):378–390. doi: 10.1038/nrm2393. [PubMed] [CrossRef] [Google Scholar]
79. Gewirtz D.A. The four faces of autophagy: implications for cancer therapy. Cancer Res. 2014;74(3):647–651. doi: 10.1158/0008-5472.Can-13-2966. [PubMed] [CrossRef] [Google Scholar]
80. Galluzzi L., Pietrocola F., Bravo-San Pedro J.M., Amaravadi R.K., Baehrecke E.H., Cecconi F., Codogno P., Debnath J., Gewirtz D.A., Karantza V., Kimmelman A., Kumar S., Levine B., Maiuri M.C., Martin S.J., Penninger J., Piacentini M., Rubinsztein D.C., Simon H.U., Simonsen A., Thorburn A.M., Velasco G., Ryan K.M., Kroemer G. Autophagy in malignant transformation and cancer progression. Embo j. 2015;34(7):856–880. doi: 10.15252/embj.201490784.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
81. Galluzzi L., Bravo-San Pedro J.M., Demaria S., Formenti S.C., Kroemer G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol. 2017;14(4):247–258. doi: 10.1038/nrclinonc.2016.183.[PubMed] [CrossRef] [Google Scholar]
82. Ravegnini G., Sammarini G., Nannini M., Pantaleo M.A., Biasco G., Hrelia P., Angelini S. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis. Autophagy. 2017;13(3):452–463. doi: 10.1080/15548627.2016.1256522.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
83. Marino G., Niso-Santano M., Baehrecke E.H., Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81–94. doi: 10.1038/nrm3735. [PMC free article][PubMed] [CrossRef] [Google Scholar]
84. Fang Y., Tian S., Pan Y., Li W., Wang Q., Tang Y., Yu T., Wu X., Shi Y., Ma P., Shu Y. Pyroptosis: A new frontier in cancer. Biomed Pharmacother. 2020;121:109595. doi: 10.1016/j.biopha.2019.109595. [PubMed] [CrossRef] [Google Scholar]
85. Gong T., Liu L., Jiang W., Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020;20(2):95–112. doi: 10.1038/s41577-019-0215-7. [PubMed] [CrossRef] [Google Scholar]
86. Liu X., Zhang Z., Ruan J., Pan Y., Magupalli V.G., Wu H., Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–158. doi: 10.1038/nature18629. [PMC free article][PubMed] [CrossRef] [Google Scholar]
88. Han S.J., Lovaszi M., Kim M., D’Agati V., Hasko G., Lee H.T. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. Faseb j. 2020;34(4):5465–5482. doi: 10.1096/fj.201903287R. [PMC free article][PubMed] [CrossRef] [Google Scholar]
89. O’Brien C.A., Kreso A., Jamieson C.H. Cancer stem cells and self-renewal. Clin Cancer Res. 2010;16(12):3113–3120. doi: 10.1158/1078-0432.CCR-09-2824.[PubMed] [CrossRef] [Google Scholar]
90. Huang Z., Wu T., Liu A.Y., Ouyang G. Differentiation and transdifferentiation potentials of cancer stem cells. Oncotarget. 2015;6(37):39550–39563. doi: 10.18632/oncotarget.6098.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
91. Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., Dewhirst M.W., Bigner D.D., Rich J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–760. doi: 10.1038/nature05236. [PubMed] [CrossRef] [Google Scholar]
92. Dean M., Fojo T., Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–284. doi: 10.1038/nrc1590.[PubMed] [CrossRef] [Google Scholar]
93. 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. J Natl Cancer Inst. 2008;100(9):672–679. doi: 10.1093/jnci/djn123. [PubMed] [CrossRef] [Google Scholar]
94. Diehn M., Clarke M.F. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. J Natl Cancer Inst. 2006;98(24):1755–1757. doi: 10.1093/jnci/djj505. [PubMed] [CrossRef] [Google Scholar]
95. 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. Mol Med Rep. 2018;17(2):3397–3403. doi: 10.3892/mmr.2017.8231. [PubMed] [CrossRef] [Google Scholar]
96. Kim J.H., Choi H.S., Kim S.L., Lee D.S. The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation. Cancers (Basel) 2019;11(10) doi: 10.3390/cancers11101527.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
97. Wang J., Seebacher N., Shi H., Kan Q., Duan Z. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. Oncotarget. 2017;8(48):84559–84571. doi: 10.18632/oncotarget.19187.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
98. 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. Expert Opin Drug Metab Toxicol. 2016;12(9):1021–1033. doi: 10.1080/17425255.2016.1196186.[PubMed] [CrossRef] [Google Scholar]
100. Kibria G., Hatakeyama H., Harashima H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res. 2014;37(1):4–15. doi: 10.1007/s12272-013-0276-2. [PubMed] [CrossRef] [Google Scholar]
101. Lespine A., Dupuy J., Orlowski S., Nagy T., Glavinas H., Krajcsi P., Alvinerie M. Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3) Chem Biol Interact. 2006;159(3):169–179. doi: 10.1016/j.cbi.2005.11.002. [PubMed] [CrossRef] [Google Scholar]
102. Pouliot J.F., L’Heureux F., Liu Z., Prichard R.K., Georges E. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Biochem Pharmacol. 1997;53(1):17–25. doi: 10.1016/s0006-2952(96)00656-9. [PubMed] [CrossRef] [Google Scholar]
103. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. Eur J Pharm Sci. 2007;30(1):84–94. doi: 10.1016/j.ejps.2006.10.004. [PubMed] [CrossRef] [Google Scholar]
104. Jiang L., Wang P., Sun Y.J., Wu Y.J. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. J Exp Clin Cancer Res. 2019;38(1):265. doi: 10.1186/s13046-019-1251-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
105. Loibl S., Gianni L. HER2-positive breast cancer. Lancet. 2017;389(10087):2415–2429. doi: 10.1016/s0140-6736(16)32417-5.[PubMed] [CrossRef] [Google Scholar]
106. Lim S.M., Syn N.L., Cho B.C., Soo R.A. Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies. Cancer Treat Rev. 2018;65:1–10. doi: 10.1016/j.ctrv.2018.02.006.[PubMed] [CrossRef] [Google Scholar]
107. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment? Cancers (Basel) 2019;11(8) doi: 10.3390/cancers11081195.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
108. Kumar R., Gururaj A.E., Barnes C.J. p21-activated kinases in cancer. Nat Rev Cancer. 2006;6(6):459–471. doi: 10.1038/nrc1892.[PubMed] [CrossRef] [Google Scholar]
109. Rane C.K., Minden A. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2019;54:40–49. doi: 10.1016/j.semcancer.2018.01.006.[PubMed] [CrossRef] [Google Scholar]
110. Dammann K., Khare V., Gasche C. Tracing PAKs from GI inflammation to cancer. Gut. 2014;63(7):1173–1184. doi: 10.1136/gutjnl-2014-306768. [PubMed] [CrossRef] [Google Scholar]
111. Kumar R., Li D.Q. PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Adv Cancer Res. 2016;130:137–209. doi: 10.1016/bs.acr.2016.01.002. [PubMed] [CrossRef] [Google Scholar]
112. Guzzo C.A., Furtek C.I., Porras A.G., Chen C., Tipping R., Clineschmidt C.M., Sciberras D.G., Hsieh J.Y., Lasseter K.C. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122–1133. doi: 10.1177/009127002401382731. [PubMed] [CrossRef] [Google Scholar]
113. Geyer J., Gavrilova O., Petzinger E. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice. J Vet Pharmacol Ther. 2009;32(1):87–96. doi: 10.1111/j.1365-2885.2008.01007.x. [PubMed] [CrossRef] [Google Scholar]
114. Gao A., Wang X., Xiang W., Liang H., Gao J., Yan Y. Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin. J Pharm Pharmacol. 2010;62(3):393–399. doi: 10.1211/jpp.62.03.0016. [PubMed] [CrossRef] [Google Scholar]
A convergence of horrifying events have set into a motion an irreversible collapse of food production and crop harvests that will lead to global famine all the way through 2024. These events cannot be stopped for the simple reason that plants take time to grow. You can’t create crops instantly, and if they don’t get planted (or they get destroyed), there’s no instant replacement.
The reasons for the coming global famine include:
Floods and droughts causing sharp drops in crop production in China, Russia and the USA, among other nations.
Economic sanctions against Russia causing a halting of exports for food and fertilizer.
War in Ukraine, leading to a halting of the 2022 planting season for wheat, corn, soy and other crops.
War in the Black Sea, blocking ship movements in the ports (such as Odessa) which normally export crops.
The Biden admin’s shutting down of fossil duel production in the USA, adding significant costs to fertilizers and agricultural operations.
Global fiat currency money printing, making food inflation reach atrocious levels.
Importantly, all this coalesces into two primary problems that will now accelerate across the world:
Scarcity, of course, means there’s no remaining supply no matter what the cost. Inflation means the food that is available will be significantly higher in price. Both of them cause people to panic, ultimately leading to widespread civil unrest (see below).
Understanding farm and crop inputs
Farmers are right now reporting a roughly 300% increase in their cost to produce crops such as wheat. This is due to three primary inputs:
The cost of fertilizer and seed.
The cost of fuel to power agricultural equipment.
The availability of tractors and other equipment (and their parts) in order to carry out mechanized agricultural operations.
Importantly, all three of these inputs are heavily strained due to the conditions mentioned above.
In addition to these factors, fuel costs significantly elevate transportation expenses to transport grains to grain storage and milling providers. Thus, rising fuel costs hit farmers twice: First for the cost of running their equipment, and secondly in the transportation costs.
Sadly, it looks like diesel fuel is headed toward $6 / gallon, and this is going to put severe upward pressure on food prices across the board. As I say in the podcast, elections have consequences… and rigged elections have dire consequences. (Joe Biden is punishing America with economic sanctions against our entire energy sector while having no such sanctions on Russia’s energy exports.)
Fertilizer costs have tripled, and fertilizer supply is growing scarce
Fertilizer prices have tripled and will likely go higher, especially as Russia has halted fertilizer exports and shut down natural gas pipelines to Western Europe. As a result, the fertilizer supply is growing scarce. About 5 billion people on the planet depend on fossil fuel-created fertilizer for their primary source of food. Thus, without fertilizer — if it were to go to zero — about 5 billion people starve to death.
I am not predicting the starvation of 5 billion people, since fertilizer production isn’t zero. But it is easily down by 25% – 30% right now, perhaps more, and that means somewhere approaching 2 billion people (or more) are going to face real famine / starvation in the crop seasons ahead. Very few people understand that food comes from fertilizer which is made using hydrocarbons. This is why left-wing activists are so eager to shut down pipelines, having no clue this will shut down their own food production as a result.
Extreme food scarcity to become apparent at the retail level this summer
There is a delay time between crop yield collapse and food scarcity at retail (grocery stores). Right now in March, we are eating the winter harvest of wheat. By late summer, we will be depending on wheat from the spring wheat crops around the world, and those crops just aren’t getting planted at the level necessary to feed the world.
The StrangeSounds.org website recently published a good overview of what they call the “wheat apocalypse.” From that article:
The wheat outlook looks grim… All over the world…
A limited supply of soft white wheat, the primary type of wheat grown in the Inland Northwest, has helped lead to a six-year low for wheat exports from the United States. That’s according to the USDA wheat report for February. The report also states that 71 percent of U.S. winter wheat is being hit by drought in 2022.
Egypt’s food security crisis now poses an existential threat to its economy. The fragile state of Egypt’s food security stems from the agricultural sector’s inability to produce enough cereal grains, especially wheat, and oilseeds to meet even half of the country’s domestic demand.
[China’s] Minister of Agriculture and Rural Affairs Tang Renjian said that rare heavy rainfall last year delayed the planting of about one-third of the normal wheat acreage.
Drought has shriveled Canada’s wheat crop to its smallest in 14 years, and its canola harvest to a nine-year low, a government report showed on Monday.
Parched soils and record-hot temperatures in Canada’s western crop belt sharply reduced farm yields of one of the world’s biggest wheat-exporting countries and largest canola-growing nation. The drought has forced millers and bakers to pay more for spring wheat, and drove canola prices to record highs.
By this summer, food shelves are going to look frighteningly empty across America, Canada and Western Europe
The upshot of all this is that food shelves are going to look downright frightening in 2022, and for the shelves that actually have food, it’s going to cost perhaps twice as much. Some items might see prices triple.
Even Reuters is now openly reporting that a United Nations agency says food inflation has hit 20%. And those are slightly old numbers. By the time they factor in the summer and fall of 2022, it’s going to be much closer to 50%.
Shockingly, food basics are going to require a larger and larger percentage of workers’ paychecks, taking away their ability to pay for fuel (which is also skyrocketing) or to purchase clothing, housing, etc.
The only factor that may actually reduce the demand for global food is the global vaccine die-off caused by mRNA / spike protein injections that are killing people are record numbers. The covid bioweapon, after all, is a depopulation weapon.
The net result is going to be global uprisings and social unrest on a scale we’ve never seen before
As covered in today’s podcast (below), the net effect of all this is going to be global uprisings, chaos and social unrest on an unprecedented scale.
Ever heard the saying about “nine meals from anarchy?” That’s what we’re about to witness later this year, in 2022.
It doesn’t mean that every city will collapse into instant chaos, but food scarcity, food inflation and energy inflation will create conditions of extreme poverty and desperation among the population. As a result, you’re going to witness more of the following:
Flash mob looting of grocery stores, followed by increased security at grocery retailers.
Gunpoint robberies of people exiting grocery stores, carrying groceries.
Highway robberies of transport trucks that are delivering goods to grocery retailers (ripped right out of Venezuela).
Increased carjackings, home invasions and crime derived from desperation and starvation. (While Democrats continue to “defund the police.”)
How Many People Died from the Covid-19 Inoculation? An Estimate Based on a Survey of the United States Population(Working Paper)
This paper examines potential fatalities and injuries from the Covid-19 inoculation using an online “Covid-19 Health Experiences Survey” administered to a representative sample of the US population. The sample is composed of 3,000 respondents balanced on age, gender, and income to the extent possible. The survey was administered in December 2021, collecting information regarding respondents’ experiences with the Covid-19 illness and the Covid-19 inoculations as well as Covid-19 health experiences within respondents’ social circles. The survey also collected respondent economic and demographic information. Using these data, I find the following:
Covid-19 inoculation-related fatalities:
Assuming that all the respondents who know somebody who they believe died from the inoculation actually died from the inoculation, estimated fatalities are about 308,000.
Subtracting out those who may have died regardless of inoculation yields an estimated 260,000 inoculation-induced fatalities. This is an initial first pass estimate—more evaluation is needed.
Factors associated with being inoculated:
The likelihood of being inoculated is significantly less for those who identify themselves as African American, Hispanic, and Asian, and Republican or Independent. Democrats, Caucasians, and more the highly educated are more likely to be inoculated.
Those who indicated that they obtain information about Covid-19 from alterative news sources were less likely to be inoculated. Those who obtain information from mainstream news and official government source are more likely to be inoculated.
Knowing someone who experienced a significant health problem from the Covid-19 illness increased the likelihood of being inoculated.
Knowing someone who had been injured by the Covid-19 inoculation substantially reduced the likelihood of being inoculated.
The official position of the US government is that the Covid-19 inoculations have resulted in nine fatalities (CDC, 2022). The experiences shared by hundreds of respondents in this survey suggests that many people died or were injured following inoculation. Which data are more believable—nine fatalities or as many as 200,000 to 300,000 fatalities? Surveys have limitations in assessing the impacts of health interventions. However, this type of evaluation offers an important point of triangulation. The experiences of people captured in surveys generally should be consistent with official government data. In the case of Covid-19 inoculations, there is a tremendous divergence which should be cause for further inquiry. My hope is that this research will motivate a full and transparent examination by independent health and medical scholars to ascertain the degree of harm being caused by the Covid-19 inoculations.
In the UK it’s estimated only 1% of adverse effects are reported. With 1.4 million in severe adverse effects and 1,900 deaths on my last check 3 weeks ago this could be enormous. I know personally 6 that have died from the vaccine and one of those was my daughter’s 23-year-old best friend. A beautiful and fun-loving working young woman taken with a brain haemorrhage.
I know endless with many severe adverse effects, 2 on chemo, two with thrombosis, 2 with thyroid and 3 with heart problems and one who was in such a mess he thought it was the end. All these people are between 23 and 50. All fit and healthy.
I would rather be locked up for life than take their poison.
3 cases have already been identified in the UK. Viral hemorrhagic (hem-uh-RAJ-ik) fevers are infectious diseases that can cause severe, life-threatening illness. They can damage the walls of tiny blood vessels, making them leak, and can hamper the blood’s ability to clot. The resulting internal bleeding is usually not life-threatening, but the diseases can be.
Ebola vs. Hemorrhagic Fever: What’s the Difference?
Collectively known as viral hemorrhagic fevers (VHFs), these illnesses typically cause fever as well as extreme dysfunction in the body’s network of blood vessels, which can result in profuse bleeding.
The hemorrhaging associated with VHFs can arise from a number of different factors depending on which virus a person is infected with, said Alan Schmaljohn, a virologist and professor of microbiology and immunology at the University of Maryland School of Medicine.
In the case of people with Ebola, hemorrhaging occurs when the virus infects the liver, affecting the body’s ability to make blood-clotting proteins and causing blood vessels to leak. But other viruses may cause hemorrhaging by depleting the body’s supply of platelets, which stop bleeding, Schmaljohn told Live Science. [5 Things You Should Know About Ebola]
Dr. Li-Meng Yan till now was ostracized and there were attempts to debunk her claims for over two years. Invariably, they turned out to be accurate. Now she comes out with another claim which is quite scary.
“The powers-that-be have attempted to debunk her claims for over two years. Invariably, they turn out to be accurate. This latest bombshell is the most concerning yet.” – JD Rucker
Below is a 24-minute video of Dr Li-meng Yan explaining everything. And there have already been 3 cases in the UK which again is blamed on West Africa, but for the last two years we have known this is coming from the CCP.
After doing over 350 interviews in my career, I rarely get shaken by a guest. That rare event occurred today when I interviewed Dr. Li-Meng Yan. She told me things from her various sources, many of which are in China with direct knowledge, that blew my mind. Is the CCP ( Chinese Communist Party ) developing another bioweapon? The answer to that is almost certainly yes, but Dr. Yan went a step further. She explained that they are already unleashing one onto the world through the Olympic games in Beijing today.
Before I get into the details, it’s important to understand that she and her sources are highly credible. There have been concerted efforts to discredit her, but her claims as far back as early 2020 have invariably been proven accurate. The powers-that-be attempted to debunk her claims that Covid-19 was developed in a lab. They tried to disprove what she’s said all along, that Peter Daszak and Anthony Fauci had intimate knowledge of the gain-of-function research that was going on in Wuhan. They even tried to prove she was wrong about the inefficacy of the vaccines. All of her claims have been verified and she has been vindicated multiple times.
She is a PhD virologist, medical doctor, immunologist and independent coronavirus expert. She was educated at two top medical schools in China, Southern Medical University and Central South University. She was also Post-doctoral Fellow in the School of Public Health at the University of Hong Kong (HKU). Because of her extensive professional network and scientific evidence, Dr. Yan has the distinction of being the only Chinese insider in the west with firsthand knowledge about the true nature of the virus as well as the Communist Chinese Party’s deceptive methods used to disguise their international bioweapons research.
Her revelations since January 19, 2020 have forced the CCP to change its strategy on the origin of SARS2 and saved many lives as a result.
Since escaping from Hong Kong on April 28, 2020, she has been interviewed four times by the FBI, including an FBI virologist, and each time she has been deemed credible. Dr. Yan had spent five years researching influenza vaccines when, in January, 2020, she was asked to investigate the ‘Wuhan Pneumonia’ that was sweeping that city. With that she became one of the first scientists outside the Wuhan Institute of Virology to analyze SARS-CoV-2. From her WHO H5 Reference Lab at HKU, she determined conclusively that the virus was engineered in the lab to be an unrestricted bioweapon. She also determined through her investigation that the spread of the virus in Wuhan was not the result of a “lab leak.”
Recognizing the great danger posed by the virus and the CCP plot to cover up its nefarious activities, Dr. Yan fled to the United States to reveal the truth to the world. Since coming to America, Dr. Yan has been the primary author of three research reports detailing the lab origins of SARS-CoV-2. Her other accomplishments include a patent-pending universal influenza vaccine as well as highly recommended articles on SARS-CoV-2 in Nature and The Lancet Infectious Diseases. Dr. Yan has attracted worldwide media attention, being interviewed by major news outlets in India, Spain, Japan, Italy and across Asia. Examples include: The Washington Post, FOX NEWS, NEWSMAX, The John Bachelor Show, The Daily Mail, Tucker Carlson Today, Tucker Carlson Tonight, Newsweek, New York Post and ITV in the UK.
The first couple of segments of our interview detailed the ways the Chinese Communist Party and other bad actors have used Covid-19 as a bioweapon. These are claims that she has detailed before, but she went into aspects of the story that were extremely compelling, including the fact that the CCP has used everyone, including her husband, to try to bring her out of hiding and take her back to China.
But it was near the middle of the interview that she blew my mind. According to Dr. Yan, CCP studied different hemorrhagic fever viruses including Lassa, Marburg, hantavirus, which all share the same drug target CD38 in the disease. Her sources show that the CCP is fully prepared to release such bioweapon viruses during the Winter Olympic. She cannot confirm what virus it is without having the viral genome.
This new disease may be a form of viral Hemorrhagic Fever that has a much higher fatality rate than Covid-19. According to Dr. Yan, cases of the disease may have been seen throughout China and just this week it popped up in the United Kingdom.
Health authorities said they have diagnosed two cases of a viral hemorrhagic fever in Britain, and possibly a third — marking the first time the illness has been seen in the country in over a decade.
Officials said the cases of Lassa fever involve members of the same family and are linked to recent travel to western Africa, where the illness is endemic. Two of the cases are conclusive and the third hasn’t been confirmed yet. Lassa fever is an acute viral hemorrhagic illness and infection usually occurs through food or household items contaminated with urine or feces from rats who are carrying the virus.
Symptoms of Lassa fever include fever and fatigue — and in more severe cases, bleeding in the mouth, trouble breathing and low blood pressure. Most people who contract Lassa fever don’t develop any symptoms and it’s fatal in only about 1% of cases. The new cases are the first in Britain since 2009.
The problem with this report is that the disease may not be standard Lassa fever, but possibly something new that was created through gain-of-function research. Dr. Yan has not confirmed this, but based on sources and evidence, Lassa is one of the bioweapons they prepared to launch attacks during or after Winter Olympics.
She noted that CCP military scientists worked with Liberia to study Ebola in 2014. They also sent six groups of scientists to Sierra Leone to study Lassa viruses, most recently in 2020. The west Africa studies by the CCP can help people understand their military-civil fusion and bioweapon program.
If she is correct, and all of her predictions have been proven accurate so far, this could mark the beginning of very troubling times in the world. Covid-19, while dangerous to the elderly with the earlier variants, seems to be rapidly fading. Governments around the world are lifting restrictions (though some, such as Canada, France, Australia, and the United States, continue to head in the other direction). It seems like the perfect time for the CCP, with the Olympics in Beijing, to spread a new bioweapon.
According to Dr. Yan, there is already a cure and the CCP is in the process of procuring as much of it as possible. It is a Johnson & Johnson drug called Darzalex (daratumumab). According to Cancer.org, the drug is currently used to treat multiple myeloma, but Dr. Yan said the CCP discovered it is effective against their new bioweapon as well.
Stay frosty, folks. The CCP has their sights set on world domination. Unleashing a dangerous disease and cornering the market on the cure may be their fast path to achieving their goals.