Solving the riddle of the sphingolipids in coronary artery disease

 Weill Cornell Medicine investigators have uncovered a way to unleash in blood vessels the protective effects of a type of fat-related molecule known as a sphingolipid, suggesting a promising new strategy for the treatment of coronary artery disease.

In the study, published in Circulation Research, the researchers showed that boosting levels of a sphingolipid called S1P in artery-lining endothelial cells slows the development and progression of coronary artery disease in an animal model. The lead author was Dr. Onorina Laura Manzo, a postdoctoral researcher in the laboratory of Dr. Annarita Di Lorenzo, an associate professor of pathology and laboratory medicine at Weill Cornell Medicine.

Sphingolipids are named for the enigmatic sphinx of ancient mythology because their functions in biology traditionally have been somewhat mysterious. In recent years, there has been increasing evidence of their relevance in coronary artery disease; bloodstream levels of S1P, for example, are lower in patients with this condition. But the precise roles of these lipids have remained unclear.

In the new study, the researchers sought a better understanding of those roles—and of sphingolipids' potential as therapeutic targets. Despite the availability of cholesterol-lowering drugs and other interventions, coronary artery disease—the underlying cause of most heart attacks and many strokes—continues to be the world's leading cause of mortality, affecting more than 20 million people in the United States alone.

Using a novel mouse model developed by the same group, the researchers found that blood pressure-related stress on arteries—which eventually will induce coronary artery disease—triggers an increase in S1P production in endothelial cells, as part of a protective response. This response normally is only temporary, but deleting a protein called NOGO-B, which inhibits S1P production, allows the rise in endothelial S1P production to be sustained—and made the animals much more resistant to coronary artery disease and associated mortality.

Another key finding is related to a different group of sphingolipids called ceramides. Prior studies have linked coronary artery disease to high bloodstream levels of some ceramides, and their causative role in the disease has been widely assumed. In their model, however, the researchers observed that while ceramide levels were high in the bloodstream, levels in artery-lining endothelial cells remained about the same regardless of coronary artery disease status. This suggests that the current view of ceramides' role in the disease should be revised.

All in all, the findings lay the foundation for the development of drugs that boost S1P to treat or prevent coronary artery disease, the researchers concluded.

More information: Onorina L. Manzo et al, Rewiring Endothelial Sphingolipid Metabolism to Favor S1P Over Ceramide Protects From Coronary Atherosclerosis, Circulation Research (2024). DOI: 10.1161/CIRCRESAHA.123.323826

https://medicalxpress.com/news/2024-04-riddle-sphingolipids-coronary-artery-disease.html

CFTC Weighs Outright Ban for Derivatives Bets on US Election

 

• Regulator is drafting a proposal for events contracts
• Agency pushes to clarify restrictions on binary options

A top Wall Street regulator is considering an outright ban on using derivatives to bet on US elections as part of a crackdown on so-called event contracts, according to people familiar with the plans.

The Commodity Futures Trading Commission’s draft proposal would boost oversight of the contracts that have let people wager on real-world outcomes such as monetary policy, lunar landings and music awards. Beyond elections, the CFTC may also prohibit some contracts on sports and calamities such as global health crises, said the people, who asked not to be identified discussing the internal deliberations.

https://www.bloomberg.com/news/articles/2024-04-24/cftc-weighs-outright-ban-for-derivatives-bets-on-us-elections

New AI technology estimates brain age using low-cost EEG device

 As people age, their brains do, too. But if a brain ages prematurely, there is potential for age-related diseases such as mild cognitive impairment, dementia, or Parkinson's disease. If "brain age" could be easily calculated, then premature brain aging could be addressed before serious health problems occur.

Researchers from Drexel University's Creativity Research Lab have developed an artificial intelligence technique that can effectively estimate an individual's brain age based on electroencephalogram (EEG) brain scans. The technology could help to make early, regular screening for degenerative brain diseases more accessible. The work is published in the journal Frontiers in Neuroergonomics.

Led by John Kounios, Ph.D., professor in Drexel's College of Arts and Sciences and Creativity Research Lab director, the research team used a type of artificial intelligence called machine learning to estimate an individual's brain age similar to the way one might guess another person's age based on their physical appearance.

"When you meet someone for the first time, you might try to estimate his or her age: Is their hair gray? Do they have wrinkles?" said Kounios. "When you learn how old they really are, you might be surprised at how young or old they look for their age and judge that they are aging more quickly or more slowly than expected."

Currently, machine-learning algorithms can learn from MRI images of healthy people's brains what features can predict the age of an individual's brain. By feeding many MRIs of healthy brains into a machine-learning algorithm along with the chronological ages of each of those brains, the algorithm can learn how to estimate the age of an individual's brain based on his or her MRI. Using this framework, Kounios and his colleagues developed the method for using EEGs instead of MRIs.

This can be thought of as a measure of general brain health, according to Kounios. If a brain looks younger than the brains of other healthy people of the same age, then there is no cause for concern. But if a brain looks older than the brains of similarly aged healthy peers, there could be premature brain aging—a "brain-age gap." Kounios explained that this kind of brain-age gap can be caused by a history of diseases, toxins, bad nutrition, and/or injuries, and can make a person vulnerable to age-related neurological disorders.

Despite brain-age estimates being a critical health marker, they have not been widely used in health care.

"Brain MRIs are expensive, and until now, brain-age estimation has been done only in neuroscience research laboratories," said Kounios. "But my colleagues and I have developed a machine-learning technology to estimate a person's brain age using a low-cost EEG system."

Electroencephalography, or EEG, is a recording of a person's brain waves. It's a less expensive and less invasive procedure than an MRI—the patient simply wears a headset for a few minutes. So, a machine learning program that can estimate brain age using EEG scans, rather than MRIs, could be a more accessible screening tool for brain health, according to Kounios.

"It can be used as a relatively inexpensive way to screen large numbers of people for vulnerability to age-related. And because of its low cost, a person can be screened at regular intervals to check for changes over time," Kounios said. "This can help to test the effectiveness of medications and other interventions. And healthy people could use this technique to test the effects of lifestyle changes as part of an overall strategy for optimizing brain performance."

Drexel University has licensed this brain-age estimation technology to Canadian health care company DiagnaMed Holdings for incorporation into a new digital health platform.

In addition to Kounios, Fengqing Zhang, Ph.D., and Yongtaek Oh, Ph.D., of Drexel University, and Jessica Fleck, Ph.D., of Stockton University contributed to this research.

More information: John Kounios et al, Brain-age estimation with a low-cost EEG-headset: effectiveness and implications for large-scale screening and brain optimization, Frontiers in Neuroergonomics (2024). DOI: 10.3389/fnrgo.2024.1340732

https://medicalxpress.com/news/2024-04-ai-technology-brain-age-eeg.html

Closed-loop drug-delivery system could improve chemo

 When cancer patients undergo chemotherapy, the dose of most drugs is calculated based on the patient's body surface area. This is estimated by plugging the patient's height and weight into an equation, dating to 1916, that was formulated from data on just nine patients.

This simplistic dosing doesn't take into account other factors and can lead to patients receiving either too much or too little of a drug. As a result, some patients likely experience avoidable toxicity or insufficient benefit from the chemotherapy they receive.

To make chemotherapy dosing more accurate, MIT engineers have come up with an alternative approach that can enable the dose to be personalized to the patient. Their system measures how much drug is in the patient's system, and these measurements are fed into a controller that can adjust the infusion rate accordingly.

This approach could help to compensate for differences in drug pharmacokinetics caused by body composition, genetic makeup, chemotherapy-induced toxicity of the organs that metabolize the drugs, interactions with other medications being taken and foods consumed, and circadian fluctuations in the enzymes responsible for breaking down chemotherapy drugs, the researchers say.

"Recognizing the advances in our understanding of how drugs are metabolized and applying engineering tools to facilitate personalized dosing, we believe, can help transform the safety and efficacy of many drugs," says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women's Hospital, and the senior author of the study.

Continuous monitoring

In this study, the researchers focused on a drug called 5-fluorouracil, which is used to treat colorectal cancers, among others. The drug is typically infused over a 46-hour period, and the dosage is determined using a formula based on the patient's height and weight, which gives the estimated body surface area.

However, that approach doesn't account for differences in body composition that can affect how the drug spreads through the body or genetic variations that influence how it is metabolized. Those differences can lead to harmful side effects if too much drug is present. If not enough drug is circulating, it may not kill the tumor as expected.

"People with the same body surface area could have very different heights and weights, could have very different muscle masses or genetics, but as long as the height and the weight plugged into this equation give the same body surface area, their dose is identical," says DeRidder, a Ph.D. candidate in the Medical Engineering and Medical Physics program within the Harvard-MIT Program in Health Sciences and Technology.

Another factor that can alter the amount of drug in the bloodstream at any given time is circadian fluctuations of an enzyme called dihydropyrimidine dehydrogenase (DPD), which breaks down 5-fluorouracil. DPD's expression, like many other enzymes in the body, is regulated on a circadian rhythm. Thus, the degradation of 5-FU by DPD is not constant but changes according to the time of the day. These circadian rhythms can lead to tenfold fluctuations in the amount of 5-fluorouracil in a patient's bloodstream over the course of an infusion.

"Using body surface area to calculate a chemotherapy dose, we know that two people can have profoundly different toxicity from 5-fluorouracil chemotherapy. Looking at one patient, they can have cycles of treatment with minimal toxicity and then have a cycle with miserable toxicity. Something changed in how that patient metabolized chemo from one cycle to the next. Our antiquated dosing fails to capture that change, and patients suffer as a result," says Douglas Rubinson, a clinical oncologist at Dana-Farber Cancer Institute and an author of the paper.

One way to try to counteract the variability in chemotherapy pharmacokinetics is a strategy called therapeutic drug monitoring, in which the patient gives a blood sample at the end of one treatment cycle. After this sample is analyzed for the drug concentration, the dosage can be adjusted, if needed, at the beginning of the next cycle (usually two weeks later for 5-fluorouracil).

This approach has been shown to result in better outcomes for patients, but it is not widely used for chemotherapies such as 5-fluorouracil.

The MIT researchers wanted to develop a similar type of monitoring, but in a manner that is automated and enables real-time drug personalization, which could result in better outcomes for patients.

In their "closed-loop" system, drug concentrations can be continually monitored, and that information is used to automatically adjust the infusion rate of the chemotherapy drug and keep the dose within the target range.

Such a closed-loop system enables personalization of the drug dose in a manner that considers circadian rhythm changes in the levels of drug-metabolizing enzymes, as well as any changes in the patient's pharmacokinetics since their last treatment, such as chemotherapy-induced toxicity of the organs that metabolize the drugs.

The new system they designed, known as CLAUDIA (Closed-Loop AUtomated Drug Infusion regulAtor), makes use of commercially available equipment for each step. Blood samples are taken every five minutes and rapidly prepared for analysis. The concentration of 5-fluorouracil in the blood is measured and compared to the target range.

The difference between the target and measured concentration is input to a control algorithm, which then adjusts the infusion rate, if necessary, to keep the dose within the range of concentrations between which the drug is effective and nontoxic.

"What we've developed is a system where you can constantly measure the concentration of drug and adjust the infusion rate accordingly to keep the drug concentration within the therapeutic window," DeRidder says.

Rapid adjustment

In tests in animals, the researchers found that using CLAUDIA, they could keep the amount of drug circulating in the body within the target range around 45 percent of the time.

Drug levels in animals that received chemotherapy without CLAUDIA remained in the target range only 13 percent of the time, on average. In this study, the researchers did not do any tests of the effectiveness of the drug levels, but keeping the concentration within the target window is believed to lead to better outcomes and less toxicity.

CLAUDIA was also able to keep the dose of 5-fluorouracil within the target range even when the researchers administered a drug that inhibits the DPD enzyme. In animals that received this inhibitor without continuous monitoring and adjustment, levels of 5-fluorouracil increased by up to eightfold.

For this demonstration, the researchers manually performed each step of the process using off-the-shelf equipment, but they now plan to work on automating each step so that the monitoring and dose adjustment can be done without any human intervention.

To measure drug concentrations, the researchers used high-performance liquid chromatography-mass spectroscopy (HPLC-MS), a technique that could be adapted to detect nearly any type of drug.

"We foresee a future where we're able to use CLAUDIA for any drug that has the right pharmacokinetic properties and is detectable with HPLC-MS, thereby enabling the personalization of dosing for many different drugs," DeRidder says.

More information: Louis B. DeRidder et al, Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing, Med (2024). DOI: 10.1016/j.medj.2024.03.020

https://medicalxpress.com/news/2024-04-loop-drug-delivery-chemotherapy.html

JPMorgan Chase caught in U.S-Russia sanctions war as overseas court orders $440 m seized from bank

 A Russian court sided with state-run lender VTB Bank in its efforts to recoup $439.5 million from JPMorgan Chase

 that the American lender froze in U.S. accounts after the Ukraine invasion.

The court ordered the seizure of funds in JPMorgan’s Russian accounts and “movable and immovable property” including the bank’s stake in a Russian subsidiary, according to a court order published Wednesday.

The order came after VTB filed a suit last week in a St. Petersburg arbitration court, seeking to be made whole for funds frozen in the United States, and asking for relief because JPMorgan has said it plans to exit Russia.

The next hearing in the Russian case is July 17.

JPMorgan declined to comment. VTB didn’t immediately respond to a request to comment.

The order was the latest example of American banks getting caught between the demands of Western sanctions regimes and overseas interests. JPMorgan is the biggest U.S. bank by assets and run by veteran CEO Jamie Dimon.  

Two years after Russia invaded Ukraine, the Biden administration has mounted an unprecedented set of sanctions, oil price caps and trade restrictions designed to weaken Moscow’s military machine.

On Wednesday, President Joe Biden signed into law a sweeping foreign aid bill that includes new powers for U.S. officials to locate and seize Russian assets in the United States. It also boosted an ongoing American effort to convince European allies to release Russian state assets to assist Ukraine.

In its own lawsuit against VTB last week in the Southern District of New York, JPMorgan sought to block VTB’s effort, noting that U.S. law prohibits the bank from releasing VTB’s $439.5 million.

This leaves JPMorgan exposed to a nearly half-billion-dollar loss, for abiding by U.S. sanctions.

The American bank, seeking to block VTB’s effort, said the Russian company broke its contractual promise to seek relief in American courts, instead finding a friendlier venue in Russia.

JPMorgan said that Russian courts have enabled similar efforts by Russian lenders against American or European banks at least a half dozen other times.

JPMorgan said it faced “certain and irreparable harm” from VTB’s efforts.

https://www.cnbc.com/2024/04/24/jpmorgan-chase-is-caught-in-us-russia-sanctions-war-after-overseas-court-orders-440-million-seized-from-bank.html

Supreme Court Takes New Step In Jan. 6 Case, Orders DOJ To Explain Themselves

 by Zachary Stieber via The Epoch Times (emphasis ours),

The U.S. Supreme Court on April 23 directed the U.S. Department of Justice to reply to a man convicted in the Jan. 6, 2021, breach of the U.S. Capitol.

Justices said the department’s response to Russell Alford is due May 23.

Mr. Alford was convicted by a jury of four misdemeanor counts but is challenging two of the charges, arguing that they don’t apply to his conduct.

The charges should not have been brought because the laws on which they’re based bar disorderly and disruptive conduct in a Capitol building and in a restricted building, but Mr. Alford merely entered the Capitol and stood silently against a wall before exiting, the Supreme Court was told in a filing from Mr. Alford’s lawyers.

U.S. District Judge Tonya Chutkan, an appointee of President Barack Obama, originally rejected Mr. Alford’s request to dismiss the counts, finding that his “mere presence inside the Capitol disturbed the public peace or undermined public safety.”

A federal appeals court, after reviewing the rejection, upheld it in January. While Mr. Alford was “neither violent nor destructive ... a jury could rationally find that his unauthorized presence in the Capitol as part of an unruly mob contributed to the disruption of the Congress’s electoral certification and jeopardized public safety,” the ruling stated.

“The court should grant review because this case presents an important question of federal statutory interpretation,” Mr. Alford’s lawyers wrote to the Supreme Court, describing the appeals court ruling as “establish[ing] a slippery and counter-textual standard for criminalizing conduct in settings for political activity.”

One of the laws, 18 U.S.C. § 1752(a)(2), bars people from “knowingly, and with intent to impede or disrupt the orderly conduct of government business or official functions, engages in disorderly or disruptive conduct in, or within such proximity to, any restricted building or grounds when, or so that, such conduct, in fact, impedes or disrupts the orderly conduct of government business or official functions.”

The other, 40 U.S.C. § 5104(e)(2)(D), makes it a crime to “utter loud, threatening, or abusive language, or engage in disorderly or disruptive conduct, at any place in the grounds or in any of the Capitol Buildings with the intent to impede, disrupt, or disturb the orderly conduct of a session of Congress or either house of Congress, or the orderly conduct in that building of a hearing before, or any deliberations of, a committee of Congress or either house of Congress.”

The lower court rulings were wrong in part because they focused on the effects of Mr. Alford’s conduct, not the nature of the conduct, according to the writ to justices.

That focus “collapses the conduct element into the harm element by giving the adjectives no apparent force,” they said. They argued later that merely being present “is not disorderly conduct unless the presence is in defiance of an order to disperse.”

If the court grants the petition, it would review the case and decide if the rulings were appropriate.

The Department of Justice’s Solicitor General, Elizabeth Prelogar, told the court on April 12 that the government was waiving its right to file a response to the filing, “unless requested to do so by the court.” The petition was distributed to justices on April 18 for their scheduled May 9 conference. Then, on Tuesday, justices directed the Department of Justice to file a response to Mr. Alford.

Lawyers for Mr. Alford and the government did not respond to requests for comment.

If justices take up the petition and rule in favor of Mr. Alford, a number of other Jan. 6 defendants and convicts could see charges thrown out.

Obstruction Charge

The court already agreed to review another charge brought against many Jan. 6 defendants.

Justices sat for oral arguments on April 16 concerning obstruction of an official proceeding, a charge brought against former police officer Joseph Fischer after he entered the Capitol on Jan. 6.

One of Mr. Fischer’s attorneys said the charge should not have been brought because the law was only intended to be used in cases of evidence tampering.

Ms. Prelogar told justices that the charge was proper because it was “not limited to evidence impairment.”

Justice Neil Gorsuch, appointed by former President Donald Trump, wondered whether the government would bring the charge against people who heckled the court.

“Would a sit-in that disrupts a trial or access to a federal courthouse qualify? Would a heckler in today’s audience qualify, or at the State of the Union address? Would pulling a fire alarm before a vote qualify for 20 years in federal prison?” he asked.

Another justice later questioned if protesters blocking access to a trial would face the charge, noting that protests have taken place in the past at the Supreme Court but the government did not charge the protesters under the law.

Ms. Prelogar said the law might apply in such cases, if there was proof of “corrupt intent.”

Justices are due to hand down a decision in the case at some point in the future.

https://www.zerohedge.com/political/supreme-court-takes-new-step-jan-6-case-orders-doj-explain-themselves

'US Steps Up Monitoring As FDA Warns Bird Flu Found In Pasteurized Milk From Grocery Stores'

 Dairy cattle moving between states must be tested for the bird flu virus, U.S. agriculture officials said Wednesday as they try to track and control the growing outbreak.

AP reports that the federal order was announced a day after health officials said they had detected inactivated remnants of the virus, known as Type A H5N1, in samples taken from milk during processing and after retail sale. They stressed that such remnants pose no known risk to people or the milk supply.

“The risk to humans remains low,” said Dawn O'Connell of the federal Administration for Strategic Preparedness and Response.

The new order requires every lactating cow to be tested and post a negative result before moving to a new state. It will help the agency understand how the virus is spreading, said Michael Watson, an administrator with the U.S. Department of Agriculture's Animal and Plant Health Inspection Service.

“We believe we can do tens of thousands of tests a day,” he told reporters.

Until now, testing had been done voluntarily and only in cows with symptoms.

As The Epoch Times' Zachary Steiber reported earlier, commercially available milk from grocery stores has tested positive for highly pathogenic avian influenza (HPAI), the U.S. Food and Drug Administration (FDA) announced on April 23.

The FDA said in a statement it has been testing milk from cattle that have been sickened with the influenza, commonly known as the bird flu or H5N1, as well as milk “in the processing system, and on the shelves.”

“Based on available information, pasteurization is likely to inactivate the virus, however, the process is not expected to remove the presence of viral particles. Therefore, some of the samples collected have indicated the presence of HPAI using quantitative polymerase chain reaction (qPCR) testing,” the agency said.

While samples tested positive, that does not mean they contain an intact pathogen, according to the FDA.

“Additional testing is required to determine whether intact pathogen is still present and if it remains infectious, which determines whether there is any risk of illness associated with consuming the product,” the FDA said.

The agency is injecting samples into fertilized chicken eggs to see whether any active virus replicates, among other experiments. It is also completing testing on samples taken from pasteurized milk from across the nation.

“To date, we have seen nothing that would change our assessment that the commercial milk supply is safe. Results from multiple studies will be made available in the next few days to weeks,” the FDA said.

The agency did not immediately respond to a request for comment for more details, including how many samples tested positive and which stores the milk that tested positive came from.

Bird flu has been confirmed in 33 herds of cattle in eight states after spreading to ruminants for the first time in the United States earlier this year, according to the U.S. Department of Agriculture. One person, a farm worker in Texas, has also tested positive for the influenza.

U.S. authorities previously said that milk from diaries with sickened animals was “being diverted or destroyed so that it does not enter the food supply” and that “pasteurization has continually proven to inactivate bacteria and viruses, like influenza, in milk,” but critics noted the authorities produced no evidence of testing to back up their position.

“There could be viruses in the milk on grocery shelves right now,” Gail Hansen, a veterinary expert who was formerly the state public health veterinarian for the Kansas Department of Health and Environment, and Andrew deCoriolis, executive director of the group Farm Forward, wrote in a recent op-ed.

Ms. Hansen said on the social media platform X that the FDA finding virus particles was “a little bit better than finding whole virus” but was “still not good.”

Rick Bright, the former director of the Biomedical Advanced Research and Development Authority at the U.S. Department of Health and Human Services, noted the shifting language from the government. The FDA now says that pasteurization “is very likely to effectively inactivate heat-sensitive viruses like H5N1 in milk from cows and other species.”

It also acknowledged that “no studies on the effects of pasteurization on HPAI viruses (such as H5N1) in bovine milk have previously been completed,” although it pointed to previous studies on effective pasteurization.

Yaneer Bar-Yam, president of the New England Complex Systems Institute, said the findings mean “milk from sick cows is being used” in the commercial supply. While pasteurization likely makes the milk safe, that safety is “not guaranteed,” he added.

Some experts emphasized that, at present, there were no indications that the positive tests meant the virus detected was infectious.

“There is no evidence to date that this is [an] infectious virus and the FDA is following up on that,” Lee-Ann Jaykus, an emeritus food microbiologist and virologist at North Carolina State University, told the Associated Press.

But Angela Rasmussen, a virologist, said on X that the positive samples “suggests there are undetected herds shedding virus into the milk supply” because they show intact virus “was once present.”

“It’s hard to say more as no raw data was shared, so we just have to take their word for it,” she added.

https://www.zerohedge.com/medical/us-steps-monitoring-fda-warns-bird-flu-found-pasteurized-milk-grocery-stores