'Cell-based approach for pulmonary arterial hypertension shown to be safe'

 Infusions of potentially therapeutic cells derived from the heart are safe for people with pulmonary arterial hypertension, a form of high blood pressure that occurs in the blood vessels of the lungs and typically affects middle-aged women, according to a study led by Cedars-Sinai investigators.

The Phase I clinical trial results are published in the peer-reviewed journal eBioMedicine, a Lancet journal.

"Although several drugs are approved for pulmonary arterial hypertension, mortality remains high," said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute at Cedars-Sinai, the Mark S. Siegel Family Foundation Distinguished Professor and senior author of the study.

"We tried a fundamentally different approach -- cell therapy delivered into the pulmonary artery -- and found encouraging results, in patients already on combination conventional therapy."

Pulmonary arterial hypertension is a rare disease, affecting fewer than 100 people per million.

There currently is no cure and the average median life expectancy on treatment for most patients is roughly 6.2 years after diagnosis.

Currently approved medications for the condition aim to open up blood vessels in the lungs, allowing for better blood flow; however, studies on lungs in patients on treatment still show severe occlusive vessel changes.

Further, these medications don't address many of the complex underlying mechanisms that cause the high pulmonary pressures.

Even on medication, people with pulmonary arterial hypertension can develop severe dysfunction in the right ventricle of the heart, the part that pumps blood to the lungs and whose function correlates best with survival.

Cedars-Sinai investigators are experimenting with using cardiosphere-derived cells (CDCs) to address some of the biological processes involved in pulmonary arterial hypertension.

CDCs were first developed and characterized by Marbán. They have been used in multiple clinical trials for a variety of diseases, most recently, Duchenne muscular dystrophy.

These are cells derived from human heart tissue that Marbán and colleagues have discovered reduce inflammation in the body and exert beneficial effects on the immune system.

Called the ALPHA study, this clinical trial was conducted in two phases.

In the first, six people with pulmonary arterial hypertension received an infusion of CDCs into their lungs.

Three patients received an infusion of 50 million CDCs and the other three received an infusion of 100 million CDCs.

In the second phase, 10 people with pulmonary arterial hypertension were randomized to receive an infusion of 100 million CDCs and 10 people were randomized to receive infusions containing a placebo.

Investigators performed right heart catheterization and cardiac MR imaging on each study participant before the infusions and four months after the infusions.

All the participants were on combination pulmonary arterial hypertension-specific medications throughout the course of the study.

The investigators tracked the health of participants for 12 months after the infusions.

No adverse effects related to the infusions occurred during this time.

Although this study was only designed to assess the safety of the CDC infusions, the investigators observed encouraging changes that might indicate the 16 people who had received the CDC infusions had improved cardiopulmonary health.

People who received the infusions, for example, showed improved functioning in the heart's right ventricle and, at two months post-infusion, were able to walk a greater distance during a six-minute test than people who received placebo.

"The most important takeaway is that this approach is safe and feasible to do in people with pulmonary arterial hypertension," said Michael I. Lewis, MD, director of Respiratory Care Services at Cedars-Sinai, and first and corresponding author of the study.

"These are encouraging exploratory findings that motivate moving on to more advanced studies."

The investigators plan additional trials to study the effects of repeated infusions of CDCs given to people with pulmonary arterial hypertension.

Cedars-Sinai investigators Mamoo Nakamura, MD; Dael Geft, MD; Yuri Matusov, MD; James Mirocha; Antoine Hage, MD; Victor Tapson, MD; Oleg A. Karpov, PhD; and Jennifer Van Eyk, PhD, also worked on the study.

Funding: The study was funded by the California Institute for Regenerative Medicine (CIRM), one of the world's largest institutions dedicated to three key areas of regenerative medicine -- research, education and patient access.

Journal Reference:

1. Michael I. Lewis, Shelley Shapiro, Ronald J. Oudiz, Mamoo Nakamura, Dael Geft, Yuri Matusov, Antoine Hage, Victor F. Tapson, Timothy D. Henry, Parisa Azizad, Rajan Saggar, James Mirocha, Oleg A. Karpov, Jennifer E. Van Eyk, Eduardo Marbán. The ALPHA phase 1 study: pulmonary ArteriaL hypertension treated with CardiosPHere-Derived allogeneic stem cells. eBioMedicine, 2023; 104900 DOI: 10.1016/j.ebiom.2023.104900

https://www.sciencedaily.com/releases/2023/12/231213133513.htm

'Enzymes can't tell artificial DNA from the real thing'

 The genetic alphabet contains just four letters, referring to the four nucleotides, the biochemical building blocks that comprise all DNA. Scientists have long wondered whether it's possible to add more letters to this alphabet by creating brand-new nucleotides in the lab, but the utility of this innovation depends on whether or not cells can actually recognize and use artificial nucleotides to make proteins.

Now, researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California San Diego have come one step closer to unlocking the potential of artificial DNA.

The researchers found that RNA polymerase, one of the most important enzymes involved in protein synthesis, was able to recognize and transcribe an artificial base pair in exactly the same manner as it does with natural base pairs.

The findings, published December 12, 2023 in Nature Communications, could help scientists create new medicines by designing custom proteins.

"Considering how diverse life on Earth is with just four nucleotides, the possibilities of what could happen if we can add more are enticing," said senior author Dong Wang, PhD, a professor at Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego.

"Expanding the genetic code could greatly diversify the range of molecules we can synthesize in the lab and revolutionize how we approach designer proteins as therapeutics."

Wang co-led the study with Steven A. Benner, PhD, at the Foundation for Applied Molecular Evolution, and Dmitry Lyumkis, PhD, at Salk Institute for Biological Studies.

The four nucleotides that comprise DNA are called adenine (A), thymine (T), guanine (G) and cytosine (C). In a molecule of DNA, nucleotides form base pairs with a unique molecular geometry called Watson and Crick geometry, named for the scientists who discovered the double-helix structure of DNA in 1953.

These Watson and Crick pairs always form in the same configurations: A-T and C-G. The double-helix structure of DNA is formed when many Watson and Crick base pairs come together.

"This is a remarkably effective system for encoding biological information, which is why serious mistakes in transcription and translation are relatively rare," said Wang.

"As we've also learned, we may be able to exploit this system by using synthetic base pairs that exhibit the same geometry."

The study uses a new version of the standard genetic alphabet, called the Artificially Expanded Genetic Information System (AEGIS), that incorporates two new base pairs.

Originally developed by Benner, AEGIS began as a NASA-supported initiative to try to understand how extraterrestrial life could have developed.

By isolating RNA polymerase enzymes from bacteria and testing their interactions with synthetic base pairs, they found that the synthetic base pairs from AEGIS form a geometric structure that resembles the Watson and Crick geometry of natural base pairs.

The result: the enzymes that transcribe DNA can't tell the difference between these synthetic base pairs and those found in nature.

"In biology, structure determines function," said Wang. "By conforming to a similar structure as standard base pairs, our synthetic base pairs can slip in under the radar and be incorporated in the usual transcription process."

In addition to expanding the possibilities for synthetic biology, the findings also support a hypothesis that dates back to Watson and Crick's original discovery.

This hypothesis, called the tautomer hypothesis, says the standard four nucleotides can form mismatched pairs due to tautomerization, or the tendency of nucleotides to oscillate between several structural variants with the same composition.

This phenomenon is thought to be one source of point mutations, or genetic mutations that only impact one base pair in a DNA sequence.

"Tautomerization allows nucleotides to come together in pairs when they aren't usually supposed to," said Wang.

"Tautomerization of mispairs has been observed in replication and translation processes, but here we provide the first direct structural evidence that tautomerization also happens during transcription."

The researchers are next interested in testing whether the effect they observed here is consistent in other combinations of synthetic base pairs and cellular enzymes.

"We are excited to assemble a multidisciplinary collaborative team with Steve and Dmitry that allow us to tackle the molecular basis of transcription on expanded alphabet," said Wang.

"There could be many other possibilities for new letters besides what we've tested here, but we need to do more work to figure out how far we can take it."

Co-authors include: Juntaek Oh, Jun Xu and Jenny Chong at UC San Diego, Zelin Shan at the Salk Institute for Biological Sciences and Shuichi Hoshika at Foundation for Applied Molecular Evolution.

Journal Reference:

1. Juntaek Oh, Zelin Shan, Shuichi Hoshika, Jun Xu, Jenny Chong, Steven A. Benner, Dmitry Lyumkis, Dong Wang. A unified Watson-Crick geometry drives transcription of six-letter expanded DNA alphabets by E. coli RNA polymerase. Nature Communications, 2023; 14 (1) DOI: 10.1038/s41467-023-43735-9

https://www.sciencedaily.com/releases/2023/12/231213212519.htm

Law enforcement internal safety alert after IEDs found at border during drug cartel gunfight

 A federal law enforcement source familiar with the issues at the US-Mexico border told FOX Business that the United States Customs and Border Protection (CBP) is warning agents to be on the lookout for explosive devices after the Mexican military reportedly seized 10 improvised explosive devices (IEDs) at the border. 

An internal officer safety alert went out on or around December 13th, warning CBP agents to be "vigilant." The IED's were found by Mexican authorities after Tucson, Arizona, border patrol agents observed gunshots at the southern border. A Tucson supervisory border patrol agent reportedly arrested an armed person on the interior of the United States who was armed with a loaded AK-47 rifle, two loaded AK magazines, loose rounds, and a handgun.

In the safety alert memo that went out to its agents, CBP warned them to "exercise extreme caution" and that they "should report any possible armed subjects approaching the border with possible explosive devices."

According to the source that spoke with FOX Business, a cartel gun fight erupted over a gap in the southern border fence at the ranch that is typically used to smuggle drugs. That area is a magnet for the cartel for human smuggling and that is what the gangs were fighting for control over.

This incident comes as FOX News reported that on Tuesday, December 12th, migrant encounters at the southern border again topped 100,000 in a single day. The numbers seen on Wednesday, December 13th, are a little less than the over 12,000 seen in a single day the week prior, which broke daily records. However, these numbers are still overwhelming CBP agents. 

According to CBP sources, Tucson and Del Rio Sectors, which saw 3,000 and 2,700 encounters, respectively, were both more than 200 percent over capacity and agents were hit by multiple groups of more than 100 migrants in multiple locations at the same time.

Lawmakers have been told that CBP agents have encountered migrants from over 150 different countries. There were more than 190 Chinese nationals encountered in the San Diego Sector alone and there were more than 120 encounters of nationals from Guinea in the Tucson Sector. 

CBP's IED warning comes as Republicans push for increased border safety measures to be included in President Joe Biden's $106 billion aid package for Israel and Ukraine. GOP lawmakers have demanded that any aid package include the entirety of H.R.2, known as "Secure the Border Act," the House signature legislation that passed in the chamber earlier this year.

The bill ramps up border security, restarts border wall construction, brings back the Remain-in-Mexico policy, and limits the use of asylum and humanitarian parole among several other changes. The bill was passed by the House back in May, but did not receive much interest from Democrats. A Senate version was later introduced by Sen. Ted Cruz (R-TX). 

Biden and Senate Democrats have rejected the sweeping southern border security bill, claiming that it would "cut off nearly all access to humanitarian protections in ways that are inconsistent with our Nation's values and international obligations."

Senate Majority Leader Chuck Schumer (D-NY) announced that the Senate would "return early" from its holiday recess to continue border talks. He said, "That will give negotiators from the White House, Senate Democrats, Senate Republicans, a time to work through the weekend in an effort to reach a framework agreement. It will then take some time to turn that framework into text."

However, Sen. James Lankford (R-OK), one of the Republicans involved in those talks, told Fox News Digital that the White House has yet to put a border proposal on paper. 

https://lawenforcementtoday.com/ieds

Applesauce pouch contamination may have been deliberate: FDA official

 “We’re still in the midst of our investigation,” Jones said in an interview with Politico. “But so far, all of the signals we’re getting lead to an intentional act on the part of someone in the supply chain and we’re trying to sort of figure that out.”

Weis, WanaBana and Schnucks are the three brands that sold the contaminated pouches and they all have ties to a manufacturing facility in Ecuador. The facility is under inspection by the FDA.

Jones told Politico he thinks the facility didn’t believe the contaminated applesauce would have ended up in countries with a robust regulatory process.

“My instinct is they didn’t think this product was going to end up in a country with a robust regulatory process,” Jones said. “They thought it was going to end up in places that did not have the ability to detect something like this.”

The FDA has continued to look into a number of theories as to why and by whom the applesauce was contaminated, but the agency currently believes it was economically motivated. Essentially, ingredients could have been altered to make products appear higher in value in order to sell them for a higher price.

Jones told Politico that despite the United States’ existing food safety laws, intentional contamination is always going to be hard to “absolutely stop.”

An FDA spokesman also said that the agency has “limited authority over foreign ingredient suppliers that do not directly ship product to the U.S. because their food undergoes further manufacturing/processing prior to export.”

Elevated levels of lead in children was first noticed by state and local officials in standard blood screenings, which are recommended by the Centers for Disease Control (CDC) to help reduce lead exposure in children under the age of 6.

“We’re going to chase that data and find whoever was responsible and hold them accountable,” Jones said.

https://thehill.com/policy/healthcare/4363214-applesauce-pouch-contamination-update-fda/

Poison control data shows significant increase in weight-loss drug overdoses

 Data from poison control centers from around the country show a large increase in calls in connection with a weight-loss and diabetes drug.

America’s Poison Centers reports around 3,000 calls in relation to semaglutide — an anti-diabetic medication — between January and November of this year, according to CNN. That is a rise of over 15-fold since 2019.

Some also reported symptoms in connection with accidental overdoses. Hospitalizations have also occurred for severe nausea, vomiting and stomach pain, the outlet reported.

Kait Brown, the clinical managing director of America’s Poison Centers, said the majority of the calls featured people reporting dosing errors.

“Oftentimes, it’s a person who maybe accidentally took a double dose or took the wrong dose,” Brown said, according to CNN.

Both weight-loss drug Wegovy and diabetes drug Ozempic share semaglutide as a key ingredient. Back in September, the U.S. Food and Drug Administration (FDA) updated the label for Ozempic, warning about more reports of a blockage of intestinal contents. 

“Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure,” the FDA wrote in an update at the time.

Wegovy now has a warning about the blockage of intestinal contents as well. 

In a statement to The Hill at the time, Novo Nordisk — the manufacturer of Ozempic — said “patient safety is a top priority,” 

“Novo Nordisk stands behind the safety and efficacy of Ozempic and all of our medicines when used consistent with the product labeling and the approved indications,” a spokesperson said.

https://thehill.com/policy/healthcare/4363267-poison-control-data-increase-weight-loss-drug-overdoses/

Pfizer mRNA Vaccine Makes 'Aberrant Proteins', Experts Concerned About Autoimmunity Events

 by Marina Zhang via The Epoch Times (emphasis ours),

There may be around a 1 in 10 chance that Pfizer mRNA COVID-19 vaccines will not generate spike proteins but something else, a new Cambridge study finds, raising concerns about autoimmune response among experts.

The study authors found that 8 percent of the time, Pfizer mRNA COVID-19 vaccines are mistranslated, leading to the formation of unintended proteins.

“Our work presents both a concern and a solution for this new type of medicine,” said leading author Anne Willis in the study’s press release.

One can think of mRNA vaccines as a set of instructions used to make spike proteins. Once the vaccine enters the cell, ribosomes interpret the mRNA instructions to make proteins, like spike proteins.

If the instructions are misinterpreted, errors in the final protein may be produced. Some errors are minor, like misspelling one word in a text, while others are more detrimental.

This misinterpretation is called a frameshift, which occurs when one or two mRNA bases are skipped. Since mRNA bases are translated in sets of threes, skipping a base would affect all the sequences downstream, leading to new proteins being formed.

“Frameshifting results in the production multiple, unique and potentially aberrant proteins,” immunologist Jessica Rose wrote in her Substack article discussing the study.

While most naturally occurring mRNA contains uridine, the Pfizer mRNA vaccines use N1-methylpseudouridine. This makes the mRNA sequence hardier and less prone to breakdown by the immune system. Pfizer’s opting for less commonly occurring mRNA bases is also why some scientists call the mRNA vaccines modified RNA, or modRNA.

By implementing additional edits to the mRNA sequences, the authors were able to reduce further frameshifted proteins.

Although "there is no evidence: that the aberrant proteins generated by Pfizer vaccination are associated with adverse outcomes, for future use of mRNA technology, it is important that "mRNA sequence design is modified" to reduce these shifts, the authors concluded.

Among Tested Vaccines, Only Pfizer Has the Issue

Apart from frameshift errors, the N1-methylpseudouridine modification can also slow down and interrupt mRNA translation to protein, potentially leading to shorter-than-expected protein sequences.

"Under ideal circumstances, ribosomes translate the vaccine mRNA into the S [spike] protein ... If the cellular machine (ribosomes) 'detect' the difference [between normal uridine and N1-methylpseudouridine], it can result in stalling or mistranslation," Dr. Adonis Sfera, assistant clinical professor of medicine at Loma Linda University, wrote to The Epoch Times via email.

In the study, the researchers first inoculated mice with both Pfizer and AstraZeneca vaccines. They found that Pfizer vaccines were significantly more likely to produce frameshifted proteins.

Researchers then compared vaccine inoculations in humans, comparing 21 participants who took the Pfizer vaccine to 20 who took the AstraZeneca vaccine. None of the AstraZeneca vaccinees had an immune reaction to proteins made from mistakes in translation, but around one-third of the Pfizer vaccinees did.

Misdirected Immunity and Autoimmunity

The authors wrote that none of the Pfizer vaccinees developed adverse effects, but they were concerned about immunological consequences.

“Mis-directed immunity has huge potential to be harmful,” immunologist Dr. James Thaventhiran, one of the study’s lead authors, said in the press release. “Off-target immune responses should always be avoided.”

The authors did not further define misdirected immunity, though it generally describes a reaction where the body’s immune system targets the wrong thing.

In this case, it can mean that rather than training the body to fight spike protein, it is trained to fight unnaturally occurring proteins instead, as highlighted by Norwegian nutritional biologist Marit Kolby in her post on X.

Additionally, some health experts are concerned that these unique proteins may increase a person’s risk of developing autoimmune disorders.

Molecular biologist professor Vladimir Uversky, PhD, from the University of South Florida and physician Dr. Alberto Rubio-Casillas concluded that autoimmunity may occur if immune cells start attacking cells producing these aberrant proteins.

"A mistranslated protein can [also] resemble a human protein and trigger antibody formation," Dr. Sfera added.

Autoimmunity occurs when the immune system attacks self-tissues. It can occur for many years before symptoms manifest.

Study findings by immunologist Aristo Vojdani suggest that spike proteins have the potential to cause cross-reactions—meaning the body accidentally targets self-tissue in a fight against other pathogens—with over 20 different human tissues, as they share structural similarities with human proteins.

The production of these aberrant proteins and peptides may also increase a person’s risks of cancer, Mr. Uversky and Dr. Rubio-Casillas added in an email to The Epoch Times.

Melanoma cells have been shown to induce frameshifted proteins to escape immune detection.

“In our opinion, there is a possibility that during the translation of mRNA from COVID-19 vaccines, the aberrant proteins generated during frameshifting could activate survival mechanisms mimicking those developed by cancer cells to escape immune surveillance,” the two added.

Unknown Proteins in the Body

Researchers currently do not know the structure or sequence of the new proteins formed.

The authors identified in the study that one of the proteins detected was a chimeric protein—one formed by joining two or more genes that originally coded for separate proteins. The chimeric protein was structurally similar to human proteins, which might induce autoimmune responses.

“Of course, nobody knows for sure that the observations are linked to harms, but the fact they theoretically might be, and that regulators seem disinterested in investigating such a possibility, should be of huge concern to all,” Dr. Jonathan Engler, co-chair of the Health Advisory and Recovery Team (HART) told The Epoch Times. HART is a UK group of academic experts sharing concerns about COVID-19-related recommendations.

“It should be emphasized that the ... paper was submitted for publication nearly a year ago, and presumably, the work was carried out some months before then. Moreover, the investigators weren’t some third-rate-university, part-time academics,” he added.

Flawed Design

Dr. Engler said that the fact that the mRNA injections can be mistranslated is a design flaw. Other experts disagree.

"People are determined to make a mountain out of this molehill," Edward Nirenberg, a medical publisher, criticized the concerns in an X post about the study.

"Frameshifts are uncommon but naturally occurring events in, for example, viral infections ... These give rise to protein products that can also be targeted by the immune system.”

However, authors of the study have highlighted in the press release that the synthetic mRNA sequence used in the vaccine was “error-prone.”

Pfizer did not respond to requests for comment.

https://www.zerohedge.com/political/pfizer-mrna-vaccine-makes-aberrant-proteins-experts-concerned-about-autoimmunity-events

GM's Cruise To Slash 24% Of Its Workforce As Part Of Restructuring

 After GM announced it was cutting back its investment in its Cruise subsidiary following a pedestrian accident earlier this year, the division now says it is cutting 24% of its workforce as part of its restructuring. 

The autonomous driving unit says it will lay off 900 of its 3,800 employees, most of whom are in the commercial operations and related corporate functions, according to Reuters. 

"This reflects our new future and a more deliberate go-to-market path, meaning less immediate need for field, commercial operations and corporate staffing," Cruise said in a statement this week. 

“GM supports the difficult employment decisions made by Cruise as it reflects their more deliberate path forward, with safety as the north star," GM said of the division during an earnings call last month. 

Recall we reported the slashing of investment in the unit about two weeks ago. The division, which had previously operated under the motto "zero crashes, zero emissions, zero congestion," announced in late November it would be cutting its budget, according to FT.

FT reported at the time that the division won't drop its slogan entirely, but will spend less on the segment. GM had previously invested about $700 million per quarter and Cruise operated in several U.S. cities, with San Francisco being the most prominent. 

Barclays auto analyst Dan Levy, speculating as to whether or not financial conditions could further mire the project, told FT at the time: "The big question is to what extent 'Zero Zero Zero' also hinged on zero rates."

"This has been a big theme this year in auto; everyone has had to step back from the euphoria," he added. 

One GM investor said in late November: "The problem for Cruise as a business is GM is dependent on it for all the software [revenue] targets the company has set. We don't see a path to profit, but we do see they will burn a lot of cash trying. GM would be better placed winding back its bet, and returning the money to shareholders."

Recall, we just in early November that about 11 days after Cruise halted all autonomous vehicle deployment across the US following several collisions and a suspension of its permit to operate robot taxis in California, Forbes revealed that Cruise CEO Kyle Vogt held an all-hands meeting to halt production of its fully autonomous vans temporarily. 

The fallout continued as Vogt, according to audio obtained by Forbes, told employees that suspending driverless operations nationwide was the primary reason why it must pause "production of the Origin" van. 

Vogt said Cruise has produced hundreds of Origin vehicles and "more than enough for the near-term when we are ready to ramp things back up." 

"During this pause, we're going to use our time wisely," he explained.

https://www.zerohedge.com/markets/gms-cruise-slash-24-its-workforce-part-restructuring