Targeting a human protein to squash SARS-CoV-2 and other viruses

 More than two years into the COVID-19 pandemic, people are realizing that the “new normal” will probably involve learning to co-exist with SARS-CoV-2. Some treatments are available, but with new variants emerging, researchers are looking toward new strategies. In ACS Infectious Diseases, scientists now report that apratoxin S4, an anticancer drug candidate that targets a human protein, can interfere with the replication of many viruses, including SARS-CoV-2 and influenza A, offering a possible pan-viral therapy.

Although COVID-19 vaccines exist, some people who received the shots have still become sick with the disease, and only a fraction of the world’s population is vaccinated. That means treatments are still needed, and a few are now available that target the virus’s RNA polymerase — the enzyme it uses to make more of its own RNA inside human cells. But some of these drugs, such as remdesivir, don’t work unless given at very early stages and can require injections.

In the hunt for new ways to treat COVID-19, various teams have revisited drugs that are already known to fight other diseases, a strategy called “repurposing.” One such preclinical stage compound is apratoxin S4 (Apra S4), which is a molecule based on a natural product that has anti-cancer activity. Previous studies have shown that apratoxins can target a human protein called Sec61, which ensures that certain proteins are properly glycosylated and folded correctly. Since viruses don’t have their own machinery to do this, they hijack the process and force human cells to make functional viral proteins. Sec61 is essential for the influenza A, HIV and dengue viruses to cause infection, so Hendrik Luesch and colleagues wondered if apratoxins could be a broadly effective, pan-viral medication that could also combat SARS-CoV-2.

In tests with monkey and human cells exposed to SARS-CoV-2, the researchers found that treatment with Apra S4 reduced the number of infected cells compared with remdesivir treatment. The molecule was also effective against influenza A, Zika virus, dengue and West Nile virus infections. Further testing revealed that Apra S4 didn’t prevent SARS-CoV-2 from entering cells, but it reduced the amount of viral protein that was produced and transported in cells, especially the spike protein, and it decreased viral RNA replication. With electron microscopy, the team observed that Apra S4 also largely blocked the formation of new viruses, with many vesicles in SARS-CoV-2-exposed monkey cells having no or very few brand-new viral particles in them. The researchers say more studies are needed, but these results suggest that Apra S4 and other inhibitors of the human Sec61 protein are broadly acting antivirals that could help in the fight against future pandemics.

The authors acknowledge funding from the National Institutes of Health, the Debbie and Sylvia DeSantis Chair professorship, the Department of Defense, the Dengue Human Immunology Project Consortium, philanthropic donations, JPB Foundation, the Open Philanthropy Project and the Swiss National Science Foundation.

The complete competing interest statement by the authors is available in the paper and by request at newsroom@acs.org.

The paper’s abstract will be available on June 29 at 8 a.m. Eastern time here: http://pubs.acs.org/doi/abs/10.1021/acsinfecdis.2c00008.

For more of the latest research news, register for our upcoming meeting, ACS Fall 2022. Journalists and public information officers are encouraged to apply for complimentary press registration by completing this form.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS’ mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and all its people. The Society is a global leader in promoting excellence in science education and providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a leader in scientific information solutions, its CAS division partners with global innovators to accelerate breakthroughs by curating, connecting and analyzing the world’s scientific knowledge. ACS’ main offices are in Washington, D.C., and Columbus, Ohio.

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JOURNAL

ACS Infectious Diseases

DOI

10.1021/acsinfecdis.2c00008 

ARTICLE TITLE

Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV‑2 and Exhibits Broad-Spectrum Antiviral Activity

ARTICLE PUBLICATION DATE

29-Jun-2022

https://www.eurekalert.org/news-releases/956906

Awake prone positioning does not offer benefit in reducing intubation for COVID-19

 A large multicenter, randomized clinical trial revealed no difference in the risk of endotracheal intubation requirement at 30 days between awake prone positioning and standard positioning for patients with COVID-19 who suffered from acute hypoxemic respiratory failure, according to research published in JAMA by researchers at UTHealth Houston.

Given the concern of limited resources during the COVID-19 pandemic, awake prone positioning, in which a non-intubated patient lies face down, was adopted as an intervention for patients with respiratory failure. When a patient is lying face down, the diseased portion, which is usually the posterior part of the lung, is no longer compressed due to gravity, which was thought to improve the overall oxygenation within the lungs. 

“Prior to the COVID-19 pandemic, it had been reported sporadically as a rescue measure, in very few case reports in different parts of the world,” said Sujith Cherian, MD, associate professor of medicine with McGovern Medical School at UTHealth Houston and director of quality for pulmonary and critical care medicine at Harris Health Lyndon B. Johnson Hospital. “This strategy was a measure in several countries, and even recommended by several medical societies, to use as a measure to improve the oxygenation to see if it would reduce the need for invasive mechanical ventilation.”

With the absence of any evidence-based strategy to guide this approach, Cherian, principal investigator of the study, and co-investigator Rosa Estrada-y-Martin, MD, professor of medicine with McGovern Medical School, wanted to see what the effects were on reducing the need for being on a ventilator. Estrada-y-Martin is also medical director of pulmonary and critical care medicine at Harris Health LBJ, the site of the Houston arm of the study. 

“Many patients that require ventilators with COVID-19 pneumonia didn't survive at the beginning of the pandemic,” said Estrada-y-Martin. “So, the idea was, what happens if we try to do something before they have to go to a ventilator?”

In addition to Harris Health LBJ, the only site in the U.S., the study was conducted at 20 other hospitals in Canada, Kuwait, and Saudi Arabia. It included adults who required at least 40% oxygen or non-invasive positive pressure ventilation and had not received invasive mechanical ventilation. The 400 patients were randomized to either the intervention group (205 participants; prone position 8-10 hours per day) or the control group (195 participants; no prone positioning). The primary outcome was endotracheal intubation within 30 days of randomization. The risk of endotracheal intubation did not significantly differ between groups (34% for prone versus 40% non-prone group) at 30 days, and the risk of mortality at 60 days was similar between the two groups (22.4% for prone versus 23.6% non-prone).

“Throughout my observation of the patients recruited for the study, it was becoming more obvious to me that the strategy helped only some patients, and it had a limited role in preventing patients from requiring mechanical ventilation,” said Cherian. “It will probably come as a surprise to several physicians because of just how widespread this measure was adopted in several countries all over the world. Moreover, one must keep in mind that it cannot be adopted as a uniform strategy in all patients and careful evaluation is necessary to identify who may benefit from this strategy. ”

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JOURNAL

JAMA

DOI

10.1001/jama.2022.7993 

ARTICLE TITLE

Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure

ARTICLE PUBLICATION DATE

15-May-2022

https://www.eurekalert.org/news-releases/957472

Could carbon monoxide foam help fight inflammation?

 Carbon monoxide is best known as a potentially deadly gas. However, in small doses it also has beneficial qualities: It has been shown to reduce inflammation and can help stimulate tissue regeneration.

A team of researchers led by MIT, Brigham and Women’s Hospital, the University of Iowa, and Beth Israel Deaconess Medical Center has now devised a novel way to deliver carbon monoxide to the body while bypassing its potentially hazardous effects. Inspired by techniques used in molecular gastronomy, they were able to incorporate carbon monoxide into stable foams that can be delivered to the digestive tract.

In a study of mice, the researchers showed that these foams reduced inflammation of the colon and helped to reverse acute liver failure caused by acetaminophen overdose. The new technique, described today in a Science Translational Medicine paper, could also be used to deliver other therapeutic gases, the researchers say.

“The ability to deliver a gas opens up whole new opportunities of how we think of therapeutics. We generally don’t think of a gas as a therapeutic that you would take orally (or that could be administered rectally), so this offers an exciting new way to think about how we can help patients,” says Giovanni Traverso, the Karl van Tassel Career Development Assistant Professor of Mechanical Engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital.

Traverso and Leo Otterbein, a professor of surgery at Harvard Medical School and Beth Israel Deaconess Medical Center, are the senior authors of the paper. The lead authors are James Byrne, a physician-scientist and radiation oncologist at the University of Iowa (formerly a resident in the Mass General Brigham/Dana Farber Radiation Oncology Program), and a research affiliate at MIT’s Koch Institute for Integrative Cancer Research; David Gallo, a researcher at Beth Israel Deaconess; and Hannah Boyce, a research engineer at Brigham and Women’s.

Delivery by foam

Since the late 1990s, Otterbein has been studying the therapeutic effects of low doses of carbon monoxide. The gas has been shown to impart beneficial effects in preventing rejection of transplanted organs, reducing tumor growth, and modulating inflammation and acute tissue injury. 

When inhaled at high concentrations, carbon monoxide binds to hemoglobin in the blood and prevents the body from obtaining enough oxygen, which can lead to serious health effects and even death. However, at lower doses, it has beneficial effects such as reducing inflammation and promoting tissue regeneration, Otterbein says.

“We’ve known for years that carbon monoxide can impart beneficial effects in all sorts of disease pathologies, when given as an inhaled gas,” he says. “However, it’s been a challenge to use it in the clinic, for a number of reasons related to safe and reproducible administration, and health care workers’ concerns, which has led to people wanting to find other ways to administer it.”

A few years ago, Traverso and Otterbein were introduced by Christoph Steiger, a former MIT postdoc and an author of the new study. Traverso’s lab specializes in developing novel methods for delivering drugs to the gastrointestinal tract. To tackle the challenge of delivering a gas, they came up with the idea of incorporating the gas into a foam, much the way that chefs use carbon dioxide to create foams infused with fruits, vegetables, or other flavors.

Culinary foams are usually created by adding a thickening or gelling agent to a liquid or a solid that has been pureed, and then either whipping it to incorporate air or using a specialized siphon that injects gases such as carbon dioxide or compressed air.

The MIT team created a modified siphon that could be attached to any kind of gas cannister, allowing them to incorporate carbon monoxide into their foam. To create the foams, they used food additives such as alginate, methyl cellulose, and maltodextrin. Xantham gum was also added to stabilize the foams. By varying the amount of xantham gum, the researchers could control how long it would take for the gas to be released once the foams were administered.

After showing that they could control the timing of the gas release in the body, the researchers decided to test the foams for a few different applications. First, they studied two types of topical applications, analogous to applying a cream to soothe itchy or inflamed areas. In a study of mice, they found that delivering the foam rectally reduced inflammation caused by colitis or radiation-induced proctitis (inflammation of the rectum that can be caused by radiation treatment for cervical or prostate cancer).

Current treatments for colitis and other inflammatory conditions such as Crohn’s disease usually involve drugs that suppress the immune system, which can make patients more susceptible to infections. Treating those conditions with a foam that can be applied directly to inflamed tissue offers a potential alternative, or complementary approach, to those immunosuppressive treatments, the researchers say. While the foams were given rectally in this study, it could also be possible to deliver them orally, the researchers say.

“The foams are so easy to use, which will help with the translation to patient care,” Byrne says.  

Controlling the dose

The researchers then set out to investigate possible systemic applications, in which carbon monoxide could be delivered to remote organs, such as the liver, because of its ability to diffuse from the GI tract elsewhere in the body. For this study, they used a mouse model of acetaminophen overdose, which causes severe liver damage. They found that gas delivered to the lower GI tract was able to reach the liver and greatly reduce the amount of inflammation and tissue damage seen there.

In these experiments, the researchers did not find any adverse effects after the carbon monoxide administration. Previous studies in humans have shown that small amounts of carbon monoxide can be safely inhaled. A healthy individual has a carbon monoxide concentration of about 1 percent in the bloodstream, and studies of human volunteers have shown that levels as high as 14 percent can be tolerated without adverse effects.

“We think that with the foam used in this study, we’re not even coming close to the levels that we would be concerned about,” Otterbein says. “What we have learned from the inhaled gas trials has paved a path to say it’s safe, as long as you know and can control how much you’re giving, much like any medication. That’s another nice aspect of this approach — we can control the exact dose.”

In this study, the researchers also created carbon-monoxide containing gels, as well as gas-filled solids, using techniques similar to those used to make Pop Rocks, the hard candies that contain pressurized carbon dioxide bubbles. They plan to test those in further studies, in addition to developing the foams for possible tests in human patients.

###

The research was funded, in part, by a Prostate Cancer Foundation Young Investigator Award, a Department of Defense Prostate Cancer Program Early Investigator Award, a Hope Funds for Cancer Research fellowship, the National Football League Players Association, the Department of Defense, and MIT’s Department of Mechanical Engineering.

 

 

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JOURNAL

Science Translational Medicine

DOI

10.1126/scitranslmed.abl4135 

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Delivery of Therapeutic Carbon Monoxide by Gas-Entrapping Materials

ARTICLE PUBLICATION DATE

29-Jun-2022

https://www.eurekalert.org/news-releases/957175

New Research Explores the Role of Oxygen in Cancer Growth

 New research published in Nature Metabolism from Columbia University and the Massachusetts Institute of Technology explores how cancer cells often depend upon the importation of fat and oxygen for continued growth and division.

Cancer cells, due to their high rate of cellular division and metabolism, have a high need for nutrients. That is one reason higher blood sugar can be a factor in cancer development, a surplus of nutrients. Diabetics, for example, have a significantly higher risk of developing cancer. In diabetic women, the risk is 27% higher than in healthy women, and in diabetic men, it’s 19% higher than in healthy men. Other essential metabolites include fat and oxygen.

Oxygen is an interesting factor because many cancer cells exist in low-oxygen environments. Because of this, there is an assumption that tumor growth is limited by energy. However, oxygen offers oxidizing power for chemical reactions that cells need to build new cells. Many of these biomolecular reactions require a co-factor dubbed NAD+. But when oxygen is absent, cells can’t regenerate NAD+, effectively stopping these biochemical reactions.

But the new research found that hypoxic (low oxygen) cancer cells have more energy than necessary for growth. As a result, when the researchers fed cancer cells extra nutrients, the cells were unresponsive.

But when the team tested other methods to affect the biomolecular pathways that were strangled by lack of oxygen, the cancer cells began to grow rapidly. What they found was that while these biosynthetic pathways struggle with little oxygen, the synthesis of fats was affected the most. Fat molecules, or lipids, are used to make new cell membranes. This seems to be another limiting factor for cancer cell growth, because, without oxygen, they can’t supply their fat synthesis pathways.

The research was led by Dennis Vitkup, Ph.D., associate professor of systems biology at Columbia University Vagelos College of Physicians, and Dr. Matthew G. Vander Heiden, M.D., Ph.D., director of the Koch Center at MIT.

“What makes our result very counterintuitive,” Vitkup said, “is that fat synthesis is not considered to be a process requiring a lot of oxygen. But our experiments demonstrated that up to 30% of the oxygen used by cancer cells is not for energy generation but for synthesizing fats.”

This means that when cancer cells are in a low oxygen environment, they are depending on importing lipids from the environment, which the researchers think might be a new target for cancer research. They are working to identify the receptors cancer cells utilize when they import lipids, and which of those receptors might be good targets for drugs. They also speculate that changing the composition of fats in the diet could play a significant role in influencing cancer growth.

“We usually think of cancer as being driven primarily by genetic mutations, but for cancer cells living in challenging conditions, such as oxygen-starvation, their environment is equally important,” Vitkup said. “Mutations stimulating uptake of fats, for example, will only promote tumor growth if these fats are actually available in their environment.”

This research refers to metabolic and molecular pathways. It might also partially explain why obesity is associated with a higher risk of getting 13 types of cancer, according to the U.S. Centers for Disease Control and Prevention. These cancers include adenocarcinoma of the esophagus, breast cancer in post-menopausal women, colorectal cancer, uterine cancer, gallbladder, upper stomach cancer and others.

Some of the risk factors tied to obesity and cancer appear to be hormone levels. Another factor is likely inflammation caused by visceral fat, which affects the hormones insulin and estrogen. But as this new research indicates, the way all of these interacts is complex, and these findings may be just the beginning.

https://www.biospace.com/article/new-research-explores-the-role-of-oxygen-in-cancer-growth/

Leaders Weigh in on how the Fall of Roe Will Affect Biopharma

 The U.S. Supreme Court’s decision to overturn Roe v. Wade has had a ripple effect on the biopharmaceutical industry. As the nation reacts, pharma companies must address the changes in demand for reproductive health drugs and services, all while navigating increasingly muddy legal waters. 

The reversal of Roe v. Wade primarily affects the pharma industry in two ways. The first, and most obvious, is the effect it will have on companies that manufacture mifepristone and misoprostol, more commonly known as the abortion pill. The second is the rise in demand for contraceptives following the SCOTUS decision. 

Medication Abortion—an Ongoing Battle

The abortion pill is actually two different pills prescribed together– first, the patient takes mifepristone, which blocks the production of progesterone and keeps the pregnancy from advancing. The patient then takes misoprostol, which causes the uterus to contract and expel anything inside.  

Medication abortions currently account for over half of all abortions in the United States, according to a study by the Guttmacher Institute published in February. Mifeprex became the first abortion pill approved by the U.S. Food and Drug Administration in 2000. And in 2019, the FDA approved a generic version of the drug.  

Unsurprisingly, medication abortions have been at the center of controversy and legal battles for years. When Mifeprex was first approved by the FDA, it could only be prescribed and dispensed in person at a hospital, clinic or doctor’s office. But when the COVID-19 pandemic hit, the American Civil Liberties Union, along with several other reproductive rights groups, sued the Trump administration and requested an emergency order to lift those regulations and allow the drug to be prescribed virtually.  

A judge granted the request, but the Supreme Court reinstated the in-person restriction after protests from the Trump administration. This back-and-forth finally came to an end in December, when the FDA permanently lifted the requirement, allowing patients to use telehealth services to get virtual prescriptions and receive them by mail.  

Now that abortion laws are regulated by the states, the FDA’s decision has called the legality of telehealth for abortion into question. Though the abortion pill is still available by mail, a patient living in a state where abortion is banned must travel to a state where it’s legal to be prescribed the medication, even if their appointment is virtual.  

Still, the Supreme Court’s decision will likely result in pharma companies that manufacture abortion pills racing to keep up with heightened demand. For almost 20 years, Danco Laboratories was the sole manufacturer of Mifeprex. But in 2019, GenBioPro’s generic version of the drug was approved by the FDA. Corcept Therapeutics is the only other FDA-approved manufacturer of the drug, but it contains a much higher dose and can only be used as a treatment for Cushing’s Syndrome.  

A spokesperson from Danco Laboratories told ABC News that Danco is prepared for any changes in demand and that it is working with federal regulators to make the drug available in pharmacies “by the end of the year.”  

"We are prepared for any surge,” the spokesperson said. “Our supply is stable and plentiful." 

A Scramble for Contraceptives

The Roe v. Wade case involved only abortions, but a decrease in access to abortion has led to a surge in demand for contraceptives, particularly emergency contraception.  

On Tuesday, CBS News reported that Wisp, an online reproductive and sexual health provider, saw a staggering 3000% increase in sales of emergency contraceptive pills following the Supreme Court’s decision. Surprisingly, Wisp CEO Ahmad Bani told CBS that so far, the company has been able to keep up with demand.  

This might be due to the time the company had to prepare, as Wisp saw a 40% increase in sales of emergency contraceptives after the draft of the SCOTUS decision was leaked in May. 

Other pharmacies are taking precautionary measures to prevent a shortage of emergency contraception. CVS said that though it has an “ample supply” of emergency contraceptives in stock, customers are limited to purchasing up to three boxes per transaction. Rite Aid followed suit, citing “increased demand” as the cause.  

For online ordering, supply is limited. Most emergency contraceptives on Amazon are not available for delivery until mid-July, and Walgreens has paused its online delivery service for contraceptives, according to The New York Times.  

Accessibility of Emergency Contraceptives– Or Lack Thereof

The most well-known emergency contraceptive is Plan B. First approved by the FDA in 1999, Plan B and its generic versions use the active ingredient levonorgestrel (LNG) to prevent pregnancy after unprotected sex. Plan B can be bought over the counter at pharmacies and retailers across the U.S. 

Though Plan B is effective, it loses its efficacy for people over 165 lbs, as well as for those who wait longer than three days after intercourse to take it. For those patients, the best alternative is ulipristal acetate, sold under the brand name ella. The drug is effective for up to five days after unprotected sex.  

But actually attaining ella is more difficult. It’s a prescription drug, so anyone who needs it must make an appointment with a physician for a prescription. After that, the next challenge is finding a pharmacy that has ella in stock.  

Dr. Sonya Borrero, a professor of medicine at the University of Pittsburgh who focuses on reproductive health equity, told NPR that she sent a team of medical students across western Pennsylvania to find out which contraceptives pharmacies keep in stock. She found that only 5% of the pharmacies they visited had ella available for immediate purchase.  

Rebecca Stone, Pharm.D., clinical associate professor at the University of Georgia School of Pharmacy and a practicing pharmacist, conducted a similar study published in December. Of the 600 pharmacies across Georgia included in the study, less than 1% had ella in stock.  

“It tends to not be readily available,” Stone said in an interview with BioSpace. “Most pharmacies will order it to be delivered the next day, but it’s more effective the sooner you take it.”  

And for those who are prescribed ella after they miss the time window for Plan B, that extra 24 hours could be too long to wait.  

Stone said she expects pharmaceutical companies to increase production to keep up with demand. But in the meantime, she urged anyone who is sexually active to use a reliable form of contraception and have emergency contraceptives on hand, just in case.  

As for the pharma industry, Stone said that while she can’t see the future, she expects some changes to be made. One of those includes a change that, on the surface, seems trivial – packaging.  

Plan B and its generics work by preventing ovulation. But the packaging for Plan B reads that it “may prevent implantation.” The label hasn’t changed since the FDA first approved the drug in 1999, though that statement has since been proven false. The packaging has already been changed in Europe to omit this statement, but the U.S. has yet to follow suit.  

“Religious groups and groups who are opposed to emergency contraception access cite [the label] as a reason for why emergency contraceptives shouldn't be available because they consider it to be more like an abortifacient,” Stone said. “But that's not supported in medicine.” 

This difference is key in understanding how emergency contraceptives work, especially as the Supreme Court’s decision has spurred debate about reproductive health services. Stone added that she and her colleagues in pharma are “trying hard to help pharmaceutical companies that manufacture this product update the packaging to reflect the current science.”  

As the nation reacts to the Roe decision, many pharma companies have benefitted from the increased demand for contraceptives. Still, the industry shouldn’t get too comfortable. As the discussion moves from abortion to contraceptives and reproductive health measures in general, these most recent changes could be only the tip of the iceberg. 

As Katie Watson, a constitutional scholar and medical ethicist at the Feinberg School of Medicine at Northwestern University told The New York Times, the pharmaceutical industry is currently in uncharted territory.  

“When people say we’re going back to the days before Roe, there’s no such thing as a time machine – we have a very different pharmaceutical landscape.” 

https://www.biospace.com/article/leaders-weigh-in-on-how-the-fall-of-roe-will-affect-biopharma-/

Known And Suspected Terrorists Entering US In Unprecedented Numbers: Rep. Higgins

 by Katabella Roberts via The Epoch Times (emphasis ours),

Known and suspected terrorists are entering the United States in unprecedented numbers amid a surge in illegal immigration, according to Rep. Clay Higgins (R-La.).

In an interview with NTD, the Louisiana representative stated that the Biden administration is providing “absurd” figures on the actual number of known and suspected terrorists entering America through its borders.

Higgins, a decorated law enforcement officer, said he believes this number to be much higher in part owing to the number of suspected terrorists who have aggressively avoided interaction with law enforcement at the border, which are referred to as “got-aways.”

Higgins’s comments come after Border Patrol agents captured 50 people who were on the FBI’s terror watchlist from October 2021 to May 2022.

That figure was just 15 in the fiscal year 2021, which included several months under former President Donald Trump’s administration.

“Towards the end of last year, I had estimated that we had lost about 250 KSTs, known and suspected terrorists, so the total numbers now that we’re told could serve about 700,000 ‘got-aways’ are suspected to have crossed into America. I think that’s a low number,” Higgins said.

“From my perspective, with data delivered to me by boots on the ground, from the border and from Central America and Mexico, and from the official numbers that are delivered to Congress from official data collection processes with Customs and Border Patrol, I think it’s reasonable for Americans to sort of step back and say, ‘My God, we have somewhere between 500 and 1,000 known and suspected terrorists [that] have entered into our country across our southern border since President [Joe] Biden has been inaugurated into office.’ This should startle every American citizen regardless of political affiliation,” Higgins said.

‘Conservative Numbers’

Explaining why he believes the actual number of suspected terrorists in the United States could be higher, Higgins, pointed to Biden’s administration, which he said is using “conservative numbers” when it comes to estimating how many there are.

The lawmaker added that this is in part because “got-aways” are very difficult to catch because they aggressively run and hide from law enforcement.

Things have been made even harder, according to Higgins, because much of law enforcement at the border has been pulled away from their primary mission of securing the border to instead processing illegal aliens, giving the “got-aways” more opportunity to escape.

“So the men that are aggressively evading law enforcement, we’re looking at true numbers of probably a million but we’ve been told 700,000,” Higgins said. “So just using a number of 700,000, and estimating that a very small percentage of that number would be a known or suspected terrorist, which fits the historical data, you could look at 700 known and suspected terrorists who have crossed into our country.”

“It’s a startling number, it should frighten us all, it should drive us to greater action to confront the Biden administration’s failed border policies to insist upon the resignation of [Department of Homeland Security] Secretary [Alejandro] Mayorkas and to promise the American people that if Mayorkas does not resign, he’s going to be impeached,” the lawmaker continued.

Higgins added that huge numbers of those individuals who are evading law enforcement at the border are working for Mexican drugs cartels, and pointed to the rising number of fentanyl deaths in America.

https://www.zerohedge.com/political/known-and-suspected-terrorists-entering-us-unprecedented-numbers-rep-higgins