Safer opioid?

 Sodium may hold the key for scientists to develop opioids or other drugs with far fewer side effects.

In a study published Wednesday by Nature, scientists from USC, Washington University in St. Louis and Stanford University have demonstrated that by chemically linking fentanyl to the sodium pockets that exist within nerve cell receptors, they could block the drug's harmful side effects and still reduce pain.

Further study is needed, but the results hold promise—not just for drug development but for addressing the nation's crisis of addiction and overdose. Nearly 70,000 Americans died in 2020 of an opioid overdose—most of them from the synthetic opioid fentanyl, according to the National Institute on Drug Abuse. In 1990s, the Food and Drug Administration approved the use of fentanyl to ease severe pain in cancer patients, but it has since made its way into the streets, worsening the national crisis of opioid abuse.

"In its current form, fentanyl is like a weapon of mass destruction," said Vsevolod Katritch, a computational scientist at the Bridge Institute at USC Michelson Center for Convergent Bioscience and a corresponding author of the study. "Our new collaborative work suggests that we could redesign the drug in such a way that we convert this frequent overdose killer to a much more benign but still effective analgesic."

Drugs of all kinds are designed to target certain receptors on nerve cells known as GCPRs, or G-coupled protein receptors, which act as signal transmitters. These receptors are like switches that mediate a drug's intended effect on the brain and body, but also the unintended side effects. In the case of fentanyl, the most potent painkiller of all opioids, patients may suffer addiction and may die from respiratory arrest.

Katritch noted that he and his fellow scientists Ray Stevens and Vadim Cherezov at the Bridge Institute and the USC Dornsife College of Letters, Arts and Sciences have been looking at the potential of the sodium mechanism since they first identified it within adenosine and opioid receptors about a decade ago.

Katritch and his collaborators said that although further study is needed to prove that their less harmful version of fentanyl will work in humans, the results have opened a new door for scientists to potentially improve the safety of painkillers.

"We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding dangerous side effects such as addiction and respiratory distress that too often lead to death," said corresponding author Susruta Majumdar of Washington University in St. Louis. "Our research is still in its early stages, but we're excited about its potential for leading to safer pain-relieving drugs."

Beyond opioid receptors, noted Katritch, this work opens a new molecular design concept for dozens of other GPCRs where such functional conversion in existing drugs would be desirable.

More information: Abdelfattah Faouzi et al, Structure-based design of bitopic ligands for the µ-opioid receptor, Nature (2022). DOI: 10.1038/s41586-022-05588-y

https://medicalxpress.com/news/2022-11-safer-opioid-scientists.html

Excess oxygen during surgery linked to higher risk of organ damage

 Giving patients excess levels of oxygen during surgery is associated with a higher risk of subsequent kidney, heart, and lung injury, finds a large U.S. study published by The BMJ today.

Although the absolute risk remains low, this study suggests it is time to reconsider the liberal use of oxygen during general anesthesia, say experts in a linked editorial.

Oxygen is routinely given to almost all patients undergoing surgery with general anesthesia to help prevent hypoxia (dangerously low oxygen levels), and the World Health Organization recommends liberal use of oxygen to reduce the risk of infection.

During surgery, arterial blood hemoglobin oxygen saturation (SpO2) is continuously measured, enabling doctors to adjust the dose of oxygen to a target level. A normal SpO2 is 94-95%. Giving oxygen in excess of that required to saturate hemoglobin—known as supraphysiological oxygen—is common.

Supraphysiological oxygen can harm the body's cells and tissues, but the clinical relevance of these effects during surgery remain uncertain, and previous trials have not been able to detect any meaningful effects on organs.

To address this knowledge gap, a team of U.S. researchers examined whether supraphysiological oxygen administration during surgery is associated with lower or higher postoperative kidney, heart, and lung injury.

Their findings are based on data for over 350,000 patients (average age 59; 52% women; 70% white) undergoing surgery with general anesthesia and endotracheal intubation (a breathing tube placed into the windpipe) at 42 medical centers across the United States between January 2016 and November 2018.

Background information on factors such as age, sex, race, weight (BMI), and medical history was collected, and patients were screened for kidney, heart, and lung injury before and after their surgery. The researchers then used an algorithm to calculate the amount of oxygen given above air level (21%) against the time spent with oxygen saturation at or above 92% throughout surgery.

Medical records were used to track cases of acute kidney, myocardial, and lung injury as well as 30 day mortality, hospital length of stay, and stroke. The average duration of surgery was 205 minutes. Acute kidney injury was diagnosed in 6.5% of patients, myocardial injury in 2.8%, and lung injury in 4.4%.

After accounting for baseline factors and other potentially influential variables, increased oxygen exposure during surgery was associated with a higher risk of organ injury.

For example, patients at the upper end (75th percentile) of oxygen levels had 26% greater odds of acute kidney injury, 12% greater odds of myocardial injury, and 14% greater odds of lung injury compared with patients at the lower end (25th percentile).

Patients at the 75th percentile of oxygen levels also had 9% greater odds of stroke and 6% greater odds of 30 day mortality than patients at the 25th percentile.

However, patients at the 75th percentile had a slightly shorter length of stay compared with patients at the 25th percentile, an effect unchanged after excluding patients who died before discharge.

These are observational findings, so can't establish cause, and the researchers acknowledge that not all patients were screened for kidney and heart injury after their surgery, nor were they able to consider factors such as diet, lifestyle, and medication use, which can influence susceptibility to organ injury.

Nevertheless, this was a large study, drawn from geographically diverse populations, ensuring precision and generalizability of the results. Findings were similar after additional analyses, providing greater confidence in their conclusions.

Based on their findings, the researchers say, "A large clinical trial to detect small but clinically significant effects on organ injury and patient centered outcomes is needed to guide oxygen administration during surgery."

This, and previous research, shows that oxygen can be a double-edged sword, point out experts in a linked editorial.

They suggest that future research on this topic could deal with some of the study's acknowledged limitations and could also measure cognitive impairment because experimental evidence suggests that brain tissue is particularly vulnerable to redox imbalance.

Research collaborations between biochemists and anesthesiologists should be encouraged, they add, "especially to identify cause-effect relationships between supraphysiological oxygen administration and organ injury."

More information: Oxygen administration during surgery and postoperative organ injury: observational cohort study, The BMJ (2022). DOI: 10.1136/bmj-2022-070941

https://medicalxpress.com/news/2022-11-excess-oxygen-surgery-linked-higher.html

Residue from rinse agents in commercial dishwashers found to destroy protective layer in gut

 Residue from rinse agents is left behind on dishes after they are cleaned in professional-grade dishwashers. This damages the natural protective layer in the gut and can contribute to the onset of chronic diseases, as demonstrated by researchers working with organoids at the Swiss Institute of Allergy and Asthma Research.

Whether it's at a restaurant, at school or in the barracks, commercial dishwashers help plates, glasses and cutlery become squeaky clean and dry in a matter of minutes. These practical benefits come with risks, however, as was recently discovered in a new study by researchers at the Swiss Institute of Allergy and Asthma Research (SIAF), an associated institute of the University of Zurich (UZH). One ingredient in particular found in commercial rinse agents has a toxic effect on the gastrointestinal tract.

Chemical residue on clean plates

A typical cycle in a commercial dishwasher involves circulating hot water and detergent for around 60 seconds at high pressure. Afterwards, there is a second 60-second washing and drying cycle in which water and a rinse agent are applied.

"What's especially alarming is that in many appliances, there's no additional wash cycle to remove the remaining rinse aid," says Cezmi Akdis, UZH professor of experimental allergology and immunology and director of the SIAF, who led the study. "This means that potentially toxic substances remain on the dishes, where they then dry in place." When the dishes are used the next time, this dried chemical residue can easily end up in the gastrointestinal tract.

This inspired the research team under Akdis to investigate what effect the components of commercial-grade detergents and rinse agents have on the epithelial barrier in the gut—the layer of cells that lines the intestinal tract and controls what enters the body. A defect in this barrier is associated with conditions such as food allergies, gastritis, diabetes, obesity, cirrhosis of the liver, rheumatoid arthritis, multiple sclerosis, autism spectrum disorders, chronic depression and Alzheimer's disease.

Similar protective layers are also present on the skin and in the lungs. As numerous studies have shown, many additives and chemicals that we encounter in everyday life can damage these layers. "We assume that defective epithelial barriers play a role in triggering the onset of two billion chronic illnesses," says Akdis. This connection is explained by the epithelial barrier hypothesis, which Akdis has helped develop during his more than 20 years of research in this field.

Toxic substance in rinse agents

The researchers used a newly developed technology for their study—human intestinal organoids and intestinal cells on microchips. The tissue forms a three-dimensional clump of cells that is very similar to the intestinal epithelium in humans. The team used various biomolecular methods to analyze the effect that commercial detergents and rinse aids have on these cells. They diluted these substances to reflect the amounts that would be present on dry dishes (1:10,000 to 1:40,000).

The result was that high doses of rinse agents killed the intestinal epithelial cells and lower doses made it more permeable. Researchers also observed the activation of several genes and cell signaling proteins that could trigger inflammatory responses. A more detailed analysis showed that one component of the rinse agent—alcohol ethoxylates—was responsible for this reaction.

According to Akdis, these findings have significant implications for public health. "The effect that we found could mark the beginning of the destruction of the gut's epithelial layer and trigger the onset of many chronic diseases," he says. Akdis calls for an immediate response: "It is important to inform the public about this risk, since alcohol ethoxylates seem to be commonly used in commercial dishwashers."

More information: Ismail Ogulur et al, Gut epithelial barrier damage caused by dishwasher detergents and rinse aids, Journal of Allergy and Clinical Immunology (2022). DOI: 10.1016/j.jaci.2022.10.020. www.jacionline.org/article/S00 … (22)01477-4/fulltext

https://medicalxpress.com/news/2022-12-residue-agents-commercial-dishwashers-destroy.html

With number of pathologists declining, can AI be used as diagnostic tool?

 One in nine women in the developed world will be diagnosed with breast cancer at some point in her life. The prevalence of breast cancer is increasing, an effect caused in part by the modern lifestyle and increased lifespans. Thankfully, treatments are becoming more efficient and more personalized. However, what isn't increasing—and is in fact decreasing—is the number of pathologists, or the doctors whose specialization is examining body tissues to provide the specific diagnosis necessary for personalized medicine.

A team of researchers at the Technion-Israel Institute of Technology has therefore made it their quest to turn computers into effective pathologists' assistants, simplifying and improving the human doctors' work. Their new study was recently published in Nature Communications.

The specific task that Dr. Gil Shamai and Amir Livne from the lab of Professor Ron Kimmel from the Henry and Marilyn Taub Faculty of Computer Science at the Technion set out to achieve lies within the realm of immunotherapy. Immunotherapy has been gaining prominence in recent years as an effective, sometimes even game-changing treatment for several types of cancer. The basis of this form of therapy is encouraging the body's own immune system to attack the tumor. However, such therapy must be personalized, as the correct medication must be administered to the patients who stand to benefit from it based on the specific characteristics of the tumor.

Multiple natural mechanisms prevent our immune systems from attacking our own bodies. These mechanisms are often exploited by cancer tumors to evade the immune system. One such mechanism is related to the PD-L1 protein—some tumors display it, and it acts as a sort of password by erroneously convincing the immune system that the cancer should not be attacked. Specific immunotherapy for PD-L1 can persuade the immune system to ignore this particular password, but of course would only be effective when the tumor expresses the PD-L1.

It is a pathologist's task to determine whether a patient's tumor expresses PD-L1. Expensive chemical markers are used to stain a biopsy taken from the tumor in order to obtain the answer. The process is non-trivial, time-consuming, and at times inconsistent. Dr. Shamai and his team took a different approach. In recent years, it has become an FDA-approved practice for biopsies to be scanned so they can be used for digital pathological analysis. Amir Livne, Dr. Shamai and Prof. Kimmel decided to see if a neural network could use these scans to make the diagnosis without requiring additional processes. "They told us it couldn't be done," the team said, "so of course, we had to prove them wrong."

Neural networks are trained in a manner similar to how children learn: they are presented with multiple tagged examples. A child is shown many dogs and various other things, and from these examples forms an idea of what "dog" is. The neural network Prof. Kimmel's team developed was presented with digital biopsy images from 3,376 patients that were tagged as either expressing or not expressing PD-L1. After preliminary validation, it was asked to determine whether additional clinical trial biopsy images from 275 patients were positive or negative for PD-L1. It performed better than expected: For 70% of the patients, it was able to confidently and correctly determine the answer. For the remaining 30% of the patients, the program could not find the visual patterns that would enable it to decide one way or the other. Interestingly, in the cases where the artificial intelligence (AI) disagreed with the human pathologist's determination, a second test proved the AI to be right.

"This is a momentous achievement," Prof. Kimmel explained. "The variations that the computer found—they are not distinguishable to the human eye. Cells arrange themselves differently if they present PD-L1 or not, but the differences are so small that even a trained pathologist can't confidently identify them. Now our neural network can."

This achievement is the work of a team comprised of Dr. Gil Shamai and graduate student Amir Livne, who developed the technology and designed the experiments, Dr. António Polónia from the Institute of Molecular Pathology and Immunology of the University of Porto, Portugal, Professor Edmond Sabo and Dr. Alexandra Cretu from Carmel Medical Center in Haifa, Israel, who are expert pathologists that conducted the research, and with the support of Professor Gil Bar-Sela, head of oncology and hematology division at Haemek Medical Center in Afula, Israel.

"It's an amazing opportunity to bring together artificial intelligence and medicine," Dr. Shamai said. "I love mathematics, I love developing algorithms. Being able to use my skills to help people, to advance medicine—it's more than I expected when I started out as a computer science student." He is now leading a team of 15 researchers, who are taking this project to the next level.

"We expect AI to become a powerful tool in doctors' hands," shared Prof. Kimmel. "AI can assist in making or verifying a diagnosis, it can help match the treatment to the individual patient, it can offer a prognosis. I do not think it can—or should—replace the human doctor. But it can make some elements of doctors' work simpler, faster, and more precise."

More information: Gil Shamai et al, Deep learning-based image analysis predicts PD-L1 status from H&E-stained histopathology images in breast cancer, Nature Communications (2022). DOI: 10.1038/s41467-022-34275-9

https://medicalxpress.com/news/2022-12-pathologists-declining-team-ai-diagnostic.html

How touch dampens the brain's response to painful stimuli

 When we press our temples to soothe an aching head or rub an elbow after an unexpected blow, it often brings some relief. It is believed that pain-responsive cells in the brain quiet down when these neurons also receive touch inputs, say scientists at MIT's McGovern Institute for Brain Research, who for the first time have watched this phenomenon play out in the brains of mice.

The team's discovery, reported Nov. 6 in the journal Science Advances, offers researchers a deeper understanding of the complicated relationship between pain and touch and could offer some insights into chronic pain in humans.

"We're interested in this because it's a common human experience," says McGovern investigator Fan Wang. "When some part of your body hurts, you rub it, right? We know touch can alleviate pain in this way." But, she says, the phenomenon has been very difficult for neuroscientists to study.

Modeling pain relief

Touch-mediated pain relief may begin in the spinal cord, where prior studies have found pain-responsive neurons whose signals are dampened in response to touch. But there have been hints that the brain was involved, too. Wang says this aspect of the response has been largely unexplored, because it can be hard to monitor the brain's response to painful stimuli amidst all the other neural activity happening there—particularly when an animal moves.

So while her team knew that mice respond to a potentially painful stimulus on the cheek by wiping their faces with their paws, they couldn't follow the specific pain response in the animals' brains to see if that rubbing helped settle it down. "If you look at the brain when an animal is rubbing the face, movement and touch signals completely overwhelm any possible pain signal," Wang explains.

She and her colleagues have found a way around this obstacle. Instead of studying the effects of face-rubbing, they have focused their attention on a subtler form of touch: the gentle vibrations produced by the movement of the animals' whiskers. Mice use their whiskers to explore, moving them back and forth in a rhythmic motion known as whisking to feel out their environment. This motion activates touch receptors in the face and sends information to the brain in the form of vibrotactile signals. The human brain receives the same kind of touch signals when a person shakes their hand as they pull it back from a painfully hot pan—another way we seek touch-mediate pain relief.

Whisking away pain

Wang and her colleagues found that this whisker movement alters the way mice respond to bothersome heat or a poke on the face—both of which usually lead to face rubbing. "When the unpleasant stimuli were applied in the presence of their self-generated vibrotactile whisking … they respond much less," she says. Sometimes, she says, whisking animals entirely ignore these painful stimuli.

In the brain's somatosensory cortex, where touch and pain signals are processed, the team found signaling changes that seem to underlie this effect. "The cells that preferentially respond to heat and poking are less frequently activated when the mice are whisking," Wang says.

"They're less likely to show responses to painful stimuli." Even when whisking animals did rub their faces in response to painful stimuli, the team found that neurons in the brain took more time to adopt the firing patterns associated with that rubbing movement. "When there is a pain stimulation, usually the trajectory the population dynamics quickly moved to wiping. But if you already have whisking, that takes much longer," Wang says.

Wang notes that even in the fraction of a second before provoked mice begin rubbing their faces, when the animals are relatively still, it can be difficult to sort out which brain signals are related to perceiving heat and poking and which are involved in whisker movement. Her team developed computational tools to disentangle these, and are hoping other neuroscientists will use the new algorithms to make sense of their own data.

Whisking's effects on pain signaling seem to depend on dedicated touch-processing circuitry that sends tactile information to the somatosensory cortex from a brain region called the ventral posterior thalamus. When the researchers blocked that pathway, whisking no longer dampened the animals' response to painful stimuli. Now, Wang says, she and her team are eager to learn how this circuitry works with other parts of the brain to modulate the perception and response to painful stimuli.

Wang says the new findings might shed light on a condition called thalamic pain syndrome, a chronic pain disorder that can develop in patients after a stroke that affects the brain's thalamus. "Such strokes may impair the functions of thalamic circuits that normally relay pure touch signals and dampen painful signals to the cortex," she says.

More information: Jinghao Lu et al, Somatosensory cortical signature of facial nociception and vibrotactile touch–induced analgesia, Science Advances (2022). DOI: 10.1126/sciadv.abn6530

https://medicalxpress.com/news/2022-12-dampens-brain-response-painful-stimuli.html

Veeva stock drops in the extended session after weaker-than-forecast quarterly guidance

 Shares of Veeva Systems Inc. dropped nearly 6% in the extended session Thursday after the cloud-computing company reported quarterly earnings above expectations but guided for a weaker-than-expected current quarter. Veeva earned $108.5 million, or 67 cents a share, in the quarter, compared with $105.9 million, or 65 cents a share, in the year-ago period. Adjusted for one-time items, the company earned $1.13 a share. Veeva's revenue rose 16% to $552.4 million, including subscription services revenue of $441.6 million, also 16% higher year-on-year. Analysts polled by FactSet expected Veeva to earn an adjusted $1.07 a share on revenue of $546 million. The results were above the company's guidance and Veeva is "well positioned for durable and profitable growth," Chief Financial Officer Brent Bowman said in a statement. Veeva, which focuses on the life-sciences industry, guided for fiscal fourth-quarter revenue between $551 million and $553 million, and adjusted EPS around $1.05. For fiscal 2023, the company called for revenue between $2.143 billion and $2.145 billion, and adjusted EPS of about $4.19. FactSet consensus for fourth quarter calls for adjusted EPS of $1.07 on revenue of $557 million, while consensus for the fiscal year calls for adjusted EPS of $4.15 on revenue of $2.142 billion. Veeva ended the regular trading day up 0.6%.

https://www.morningstar.com/news/marketwatch/202212011038/veeva-stock-drops-in-the-extended-session-after-weaker-than-forecast-quarterly-guidance

FDA approves Rigel Pharma’s leukemia treatment

 Rigel Pharmaceuticals said on Thursday the U.S. Food and Drug Administration has approved its drug for the treatment of patients with a type of leukemia.

https://kfgo.com/2022/12/01/u-s-fda-approves-rigel-pharmas-leukemia-treatment/