NATO Fractures: In U-Turn, Poland Announces It Will No Longer Arm Ukraine

 The dam is breaking on unified Western support for Ukraine, and the timing couldn't be worse for Zelensky, given tomorrow he's expected to meet with President Biden at the White House. On Wednesday evening there is monumental news out of Poland which could potentially change the entire course of the war.

"Poland will no longer arm Ukraine to focus on its own defense," Polish prime minister Mateusz Morawiecki announced just hours after Warsaw summoned Ukraine's ambassador related to a fresh war of words and spat over blocked grain, according to the AFP. Warsaw has throughout more than a year-and-a-half of the Ukraine-Russia war been Kiev's staunchest and most outspoken supporter.

Will this massive and hugely significant about-face mark the beginning of the end? Are peace negotiations and ceding of territory in the Donbas inevitable at this point? 

Within the last 48 hours relations between Poland and Ukraine quickly spiraled to their lowest point since the Russian invasion, and it is directly related to Warsaw leading a handful of EU countries to extend a grain export ban on Ukraine, amid continuing anger and outrage from Polish farmers who are suffering due to their country being flooded with cheap Ukrainian wheat.

Crucially, Poland will hold parliamentary elections on Oct.15. The prior atmosphere of enthusiastic pro-Kiev rhetoric has drastically changed, now with comparisons likening Ukraine to a "drowning man". As The Associated Press explains:

Polish leaders have compared Ukraine to a drowning person hurting his helper and threatened to expand a ban on food products from the war-torn country. Meanwhile, Ukrainian President Volodymyr Zelenskyy suggested that EU allies that are prohibiting imports of his nation’s grain are helping Russia.

Now, Polish officials, who are trying to win parliamentary elections next month with help from farmers’ votes, are expressing dismay over some of Ukraine’s latest moves, including a World Trade Organization complaint over bans on Ukrainian grain from Poland and two other EU countries.

In surprisingly blunt and terse words given to reporters on the sidelines of the UN General Assembly, Polish President Andrzej Duda said on Tuesday: "Ukraine is behaving like a drowning person clinging to anything available."

He then said, "A drowning person is extremely dangerous, capable of pulling you down to the depths … simply drown the rescuer." Given Ukraine's battlefield losses and as it's currently bogged down in a failing counteroffensive, the words no doubt stung. But as The Hill notes further of the domestic political context in Poland:

Public sentiment around the issue, however, has started to deteriorate, putting the ruling party in a difficult position ahead of a close October election. The far-right Confederation party is hoping to capitalize on the waning support in the country. 

Reuters reported that a recent poll showed support for Ukrainian refugees fell from 91 percent when the war started to just 69 percent recently. The same survey showed a quarter of Poles are against supporting refugees, compared to 4 percent in early 2022.

In response to the grain ban, Zelensky during his UN speech had condemned the "alarming" behavior of allies regarding the import ban, but without naming Poland specifically. Further, Kiev has announced plans to sue Warsaw in the World Trade Organization while also holding out the possibility of its own embargo on Polish foodstuffs, including onions, tomatoes, cabbage, and apples. Again, all of this amounts to a full-blown diplomatic crisis for Zelensky which couldn't come at a worse time, as he's in D.C.

To review, these are some of the major developments and setbacks in only the last few days:

• Zelensky fired at least 6 top-ranking defense officials over corruption, after recently firing longtime Defense Minister Oleksii Reznikov amid a graft probe.
• American transgender spokesperson for Ukraine's Territorial Defense Forces Sarah Ashton-Cirillo was suspended indefinitely by the Ukrainian military in an embarrassing debacle.
• The New York Times ran an article which said a missile fired by Ukraine - not Russia - struck a busy civilian market ...marking an unexpected establishment media about-face.
• Biden has yet to pledge any new weapons for Ukraine as Zelensky is in the US, and there are reports that ATACMS long-range missiles will not be approved.

And most importantly, there's this per Politico...

According to the fresh Wednesday report:

Delivering any new aid to help defend against Russia, even later this year, is looking tougher than ever.

The obstacles are piling up: House Republicans are skeptical of any new money at all. What’s more, their dysfunction threatens to push the government into a shutdown — a move that certainly gets Zelenskyy no closer to getting the billions requested by the Biden administration. Senate Republicans, meanwhile, are divided over whether to continue providing humanitarian aid, arguing the rest of Europe needs to step up.

As if fully aware that the tap at the expense of the US taxpayer may run dry, Zelensky has been meeting in New York with a who's who of leading banks, hedge funds, and private investors. Fox Business, which broke the story, says the ongoing meetings are part of broader efforts to secure investment for rebuilding Ukraine and fixing destroyed infrastructure:  

The meeting was put together by JPMorgan, the big bank serving as Zelenskyy’s financial adviser to attract private capital for a new investment fund to rebuild Ukraine’s infrastructure destroyed in its war with Russia, according to people with knowledge of the matter. 

Earlier in the afternoon, Zelenskyy met privately with BlackRock CEO Larry Fink, the sources say. BlackRock is the world’s largest asset manager and has also been advising Zelenskyy on how to attract U.S. private sector money for the rebuilding effort.

The list of invitees, according to sources, includes William Ackman, the head of hedge fund Pershing Square Capital; Ken Griffin of the Citadel investment empire; Jonathan Gray, president and chief operating officer of private equity powerhouse Blackstone; Philipp Hildebrand, a vice chairman at BlackRock; Michael Bloomberg, former New York City mayor and founder of Bloomberg LP; and Eric Schmidt, the former CEO of Google and now head of the Schmidt Futures, a philanthropic organization.

Tomorrow's White House visit, and Zelensky's planned meeting with Republican House Speaker Kevin McCarthy will surely be interesting.

Meanwhile, for a foretaste and indicator of how much the tide is turning - and the very different, subdued optics - especially compared to Zelensky's last trip to Washington (in Dec. 2022) when he was received with rockstar status, there's this...

https://www.zerohedge.com/geopolitical/nato-fractures-u-turn-poland-announces-will-no-longer-arm-ukraine

China’s Health-Care Tycoons Lose $17 Billion as Crackdown Spreads

 

• Sweeping anti-graft campaign sends shares in sector tumbling
• Aier Eye Hospital chairperson Chen Bang slides $3.4 billion

China’s latest anti-corruption crackdown is hammering the personal wealth of the nation’s health-care tycoons.

The combined fortunes of the top 15 Chinese health-care billionaires has fallen to $84.1 billion from $101.4 billion at the end of last year, according to the Bloomberg Billionaires Index.

https://www.bloomberg.com/news/articles/2023-09-20/china-health-care-tycoons-lose-17-billion-as-crackdown-on-corruption-spreads

Tracking down the formation of cardenolides in plants

 Scientists at the Max Planck Institute for Chemical Ecology in Jena are investigating the previously largely unknown biosynthetic pathway that leads to the formation of cardenolides in plants. In a study published in the journal Nature Plants, they present two enzymes from the CYP87A family as key enzymes that catalyze the formation of pregnenolone, the precursor for the biosynthesis of plant steroids, in two different plant families. The discovery of such enzymes should help to develop platforms for the cheap and sustainable production of high quality steroid compounds for medical use.

Plants produce an impressive array of metabolites, including many medically valuable steroids. Well-known examples of this class of substances obtained from plants are cardenolides. As early as 1785, the British physician William Withering (1741-1799) published a book on the red foxglove and its use in medicine (An account of the foxglove, and some of its medical uses: with practical remarks on dropsy, and other diseases. Birmingham 1785). He had found out in experiments that taking extracts of the plant increased the flow of urine in sick people, thus treating water retention in the body. However, he did not know that the active ingredients in foxglove leaves had a direct effect on the heart. Since the second half of the 19th century, cardenolides, cardiac glycosides from plants, have been used to treat of heart failure or arrhythmia because of their effect on the heart muscle.

"In addition to their effect on the contractility of the heart, cardenolides have been used with great success in recent years for the treatment of various cancers. However, the corresponding plant biosynthetic pathways have remained largely unknown despite the success of these steroid molecules in human medicine. Our goal was therefore to understand how plants synthesize these highly complex molecules from predicted but simple precursors," explains first author Maritta Kunert.

In addition to foxglove Digitalis purpurea, the research team also studied another plant species, the rubber tree Calotropis procera. Although these two plants belong to different plant families, they both produce large amounts of cardenolides. Since the species studied are not model plants whose genomes have been sequenced and for which many gene functions are known, the project was initially something of a "black box" for the researchers, as they had no existing data sets or standard methods to fall back on. The starting point for the study was earlier work in a related species of foxglove, which suggested that the biosynthesis occurred via the molecule pregnenolone, sometimes referred to as the "mother of all steroid hormones" because all major steroid hormones such as testosterone, progesterone and estrogen in humans can be traced back to the precursor pregnenolone.

"We identified the candidate genes involved in cardenolide biosynthesis by comparative analysis of the two plant species. The structures of the cardenolides in these plants have both overlapping and divergent profiles. Therefore, comparing information about the plants' genomes, in particular which genes are expressed in these two plants in relation to the formation of metabolites, was very helpful in identifying the enzymes involved in the formation of pregnenolone," says study leader Prashant Sonawane, who heads the project group "Steroidal Specialised Metabolism in Plants" in the Department of Natural Product Biosynthesis.

In addition, the scientists did not even know where the metabolites of interest were accumulated in the different parts of plants. "The tissue-specific localization of the cardenolides was crucial for using the genetic data sets in a way that allowed the selection of 13 candidate genes. Comparing these datasets across different plants helped us to reduce the number of candidate genes for further characterization," explains Prashant Sonawane.

Finally, two enzymes of the cytochrome P450 family 87A were identified that catalyze the conversion of both cholesterol and phytosterols into pregnenolone in foxglove and Calotropis procera. This was the first step in the cardenolide biosynthetic pathway in these two only distantly related plants. Importantly, this is the first enzymatic function reported for this subfamily of cytochrome P450.

The scientists tested their findings by modifying plants of the model system Arabidopsis thaliana to produce more CYP87A enzymes. The genetically modified Arabidopsis plants accumulated unusually high levels of pregnenolone. Further evidence for the involvement of CYP87A enzymes in the formation of pregnenolone came from genetically modified foxglove plants that lacked CYP87A enzymes in their leaves. In these plants, the formation of pregnenolone and cardenolides was greatly reduced. The authors established the first stable transformation system to modify foxglove plants for the study of specialised metabolites.

The research team is far from satisfied with deciphering the first enzymatic step of cardenolide biosynthesis. "We are already working on the downstream steps for the formation of cardenolides in different plant species. This biosynthetic pathway is long and highly complex. With the ability to apply the latest sequencing, bioinformatics and metabolomics methods across multiple plant species, we hope to solve this puzzle soon," says Prashant Sonawane.

Plants produce many pharmaceutical compounds. The extraction of these natural products is still very complex and often not very sustainable. The Department of Natural Product Biosynthesis at the Max Planck Institute for Chemical Ecology, led by Sarah O'Connor, aims to elucidate the biosynthetic pathways of important phytochemicals with medical relevance. "The discovery of enzymes such as CYP87A can help develop biological platforms for the sustainable production of high-value plant compounds by using other plants for their biosynthesis," says Sarah O'Connor.

Journal Reference:

1. Maritta Kunert, Chloe Langley, Rosalind Lucier, Kerstin Ploss, Carlos E. Rodríguez López, Delia A. Serna Guerrero, Eva Rothe, Sarah E. O’Connor, Prashant D. Sonawane. Promiscuous CYP87A enzyme activity initiates cardenolide biosynthesis in plants. Nature Plants, 2023; DOI: 10.1038/s41477-023-01515-9

https://www.sciencedaily.com/releases/2023/09/230918153157.htm

Crucial biomarker that tracks recovery from treatment-resistant depression

A team of leading clinicians, engineers, and neuroscientists has made a groundbreaking discovery in the field of treatment-resistant depression. By analyzing the brain activity of patients undergoing deep brain stimulation (DBS), a promising therapy involving implanted electrodes that stimulate the brain, the researchers identified a unique pattern in brain activity that reflects the recovery process in patients with treatment-resistant depression. This pattern, known as a biomarker, serves as a measurable indicator of disease recovery and represents a significant advance in treatment for the most severe and untreatable forms of depression.

The team's findings, published online in the journal Natureon September 20, offer the first window into the intricate workings and mechanistic effects of DBS on the brain during treatment for severe depression.

DBS involves implanting thin electrodes in a specific brain area to deliver small electrical pulses, similar to a pacemaker. Although DBS has been approved and used for movement disorders such as Parkinson's disease for many years, it remains experimental for depression. This study is a crucial step toward using objective data collected directly from the brain via the DBS device to inform clinicians about the patient's response to treatment. This information can help guide adjustments to DBS therapy, tailoring it to each patient's unique response and optimizing their treatment outcomes.

Now, the researchers have shown it's possible to monitor that antidepressant effect throughout the course of treatment, offering clinicians a tool somewhat analogous to a blood glucose test for diabetes or blood pressure monitoring for heart disease: a readout of the disease state at any given time. Importantly, it distinguishes between typical day-to-day mood fluctuations and the possibility of an impending relapse of the depressive episode.

The research team, which includes experts from the Georgia Institute of Technology, the Icahn School of Medicine at Mount Sinai, and Emory University School of Medicine, used artificial intelligence (AI) to detect shifts in brain activity that coincided with patients' recovery.

The study, funded by the National Institutes of Health Brain Research Through Advancing Innovative Neurotechnologies ®, or the BRAIN Initiative ®, involved 10 patients with severe treatment-resistant depression, all of whom underwent the DBS procedure at Emory University. The study team used a new DBS device that allowed brain activity to be recorded. Analysis of these brain recordings over six months led to the identification of a common biomarker that changed as each patient recovered from their depression. After six months of DBS therapy, 90 percent of the subjects exhibited a significant improvement in their depression symptoms and 70 percent no longer met the criteria for depression.

The high response rates in this study cohort enabled the researchers to develop algorithms known as "explainable artificial intelligence" that allow humans to understand the decision-making process of AI systems. This technique helped the team identify and understand the unique brain patterns that differentiated a "depressed" brain from a "recovered" brain.

"The use of explainable AI allowed us to identify complex and usable patterns of brain activity that correspond to a depression recovery despite the complex differences in a patient's recovery," explained Sankar Alagapan PhD, a Georgia Tech research scientist and lead author of the study. "This approach enabled us to track the brain's recovery in a way that was interpretable by the clinical team, making a major advance in the potential for these methods to pioneer new therapies in psychiatry."

Helen S. Mayberg, MD, co-senior author of the study, led the first experimental trial of subcallosal cingulate cortex (SCC) DBS for treatment-resistant depression patients in 2003, demonstrating that it could have clinical benefit. In 2019, she and the Emory team reported the technique had a sustained and robust antidepressant effect with ongoing treatment over many years for previously treatment-resistant patients.

"This study adds an important new layer to our previous work, providing measurable changes underlying the predictable and sustained antidepressant response seen when patients with treatment-resistant depression are precisely implanted in the SCC region and receive chronic DBS therapy," said Dr. Mayberg, now Founding Director of the Nash Family Center for Advanced Circuit Therapeutics at Icahn Mount Sinai. "Beyond giving us a neural signal that the treatment has been effective, it appears that this signal can also provide an early warning signal that the patient may require a DBS adjustment in advance of clinical symptoms. This is a game changer for how we might adjust DBS in the future."

"Understanding and treating disorders of the brain are some of our most pressing grand challenges, but the complexity of the problem means it's beyond the scope of any one discipline to solve," said Christopher Rozell, PhD, Julian T. Hightower Chair and Professor of Electrical and Computer Engineering at Georgia Tech and co-senior author of the paper. "This research demonstrates the immense power of interdisciplinary collaboration. By bringing together expertise in engineering, neuroscience, and clinical care, we achieved a significant advance toward translating this much-needed therapy into practice, as well as an increased fundamental understanding that can help guide the development of future therapies."

The team's research also confirmed a longstanding subjective observation by psychiatrists: as patients' brains change and their depression eases, their facial expressions also change. The team's AI tools identified patterns in individual facial expressions that corresponded with the transition from a state of illness to stable recovery. These patterns proved more reliable than current clinical rating scales.

In addition, the team used two types of magnetic resonance imaging to identify both structural and functional abnormalities in the brain's white matter and interconnected regions that form the network targeted by the treatment. They found these irregularities correlate with the time required for patients to recover, with more pronounced deficits in the targeted brain network correlated to a longer time for the treatment to show maximum effectiveness. These observed facial changes and structural deficits provide behavioral and anatomical evidence supporting the relevance of the electrical activity signature or biomarker.

"When we treat patients with depression, we rely on their reports, a clinical interview, and psychiatric rating scales to monitor symptoms. Direct biological signals from our patients' brains will provide a new level of precision and evidence to guide our treatment decisions," said Patricio Riva-Posse, MD, Associate Professor and Director of the Interventional Psychiatry Service in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine, and lead psychiatrist for the study.

Given these initial promising results, the team is now confirming their findings in another completed cohort of patients at Mount Sinai. They are using the next generation of the dual stimulation/sensing DBS system with the aim of translating these findings into the use of a commercially available version of this technology.

Journal Reference:

1. Sankaraleengam Alagapan, Ki Sueng Choi, Stephen Heisig, Patricio Riva-Posse, Andrea Crowell, Vineet Tiruvadi, Mosadoluwa Obatusin, Ashan Veerakumar, Allison C. Waters, Robert E. Gross, Sinead Quinn, Lydia Denison, Matthew O’Shaughnessy, Marissa Connor, Gregory Canal, Jungho Cha, Rachel Hershenberg, Tanya Nauvel, Faical Isbaine, Muhammad Furqan Afzal, Martijn Figee, Brian H. Kopell, Robert Butera, Helen S. Mayberg, Christopher J. Rozell. Cingulate dynamics track depression recovery with deep brain stimulation. Nature, 2023; DOI: 10.1038/s41586-023-06541-3

https://www.sciencedaily.com/releases/2023/09/230920111250.htm

Alternative pain control circuits in brain produce relief similar to opioids without downsides

 The opioid epidemic in the United States has exacted an incalculable toll on individuals and communities, creating an urgent need for alternative painkillers. The search for non-opioid treatments is crucial, not only to mitigate the risks of addiction and overdose, but also to develop pain management tools that remain effective without inducing tolerance and other challenging side effects in patients.

New research from the University of Chicago identified an alternative signaling pathway in the brain of mice that relieves pain, even in animals that have developed tolerance to opioids.

The study, titled "A Cholinergic Circuit That Relieves Pain, Despite Opioid Tolerance" and published in Neuron, also showed that pain relief through this route did not induce tolerance, did not create withdrawals symptoms after treatment was stopped, and did not activate reward systems, limiting risk for addiction and making it a viable path to developing effective, non-opioid pain relief.

"There are multiple categories of non-opioid treatments, but the bad news is that nothing currently compares to opioids for the level of pain relief," said Daniel McGehee, Ph.D., Professor of Anesthesia and Critical Care at UChicago and senior author of the new study. "Any alternative is a welcome option, and we have found pain control circuitry here that can produce relief similar to what we see with opioid activity, without the downsides."

A different circuit for pain relief

The ventrolateral periaqueductal gray (vlPAG) is an area of the brain that serves as an important crossroads of systems that control pain. Previous research has shown that electrical stimulation and pharmacological treatments targeting this region can relieve pain, although the non-opioid circuits that alter pain through changes in activity in this part of the brain are less well-studied.

One of these circuits involves the neurotransmitter acetylcholine, which affects activity in multiple parts of the brain. Targeting acetylcholine receptors can change pain responses, but the mechanisms by which naturally produced acetylcholine regulates pain control circuitry in the vIPAG had not been explored.

McGehee and Shivang Sullere, Ph.D., a previous graduate student in the Committee on Neurobiology at UChicago, now a postdoctoral scholar at the Harvard Medical School and the new study's first author, investigated the dynamics of how acetylcholine is released in this area of the brain under various pain states, like inflammation, chronic neuropathy, or acute pain.

McGehee's lab published a paper in 2017 showing that targeting an acetylcholine receptor in the vIPAG called alpha-7 (⍺7) produced an analgesic effect. One might expect that the body would take advantage of this and release more acetylcholine in a painful scenario, but instead, the researchers saw the opposite effect—it was being suppressed. The team then set out to understand how and why this was happening.

The ⍺7 receptor is usually an excitatory receptor, meaning that it generates more activity in the nervous system. But when the researchers injected a drug that stimulates ⍺7 into the mice, the cells' initial excited state quickly gave way to a prolonged quiet state, producing an analgesic effect that lasted for several hours.

"That was a huge and extremely unexpected outcome," McGehee said. "Persistent inhibition was not on our radar at all. It was always a conundrum to me, but we saw that there is recruitment of another signaling pathway that is altering potassium channel function and causing these cells to shut down."

When the team tested the effects of boosting acetylcholine in mice that had tolerance to opioids, they saw the same long-lasting analgesic effects. That's because the acetylcholine receptor is part of a different pathway than that used by opioids—the two operate independently, and if tolerance develops in the opioid circuits, acetylcholine's effects are not altered.

The animals also didn't show signs of dependence or preference for environments where they received the drug that stimulated more acetylcholine in the absence of pain, which is a good sign that it doesn't have addictive properties.

Separate imaging experiments also showed that higher levels of activity in cells that express ⍺7 correlated with higher levels of pain experienced by the animals: when those same cells were suppressed, pain was reduced as well.

"Not only do these cells relieve pain, they also accurately mirror the pain state of the organism. Through imaging methods, we can reproducibly monitor these neurons and acetylcholine in the vlPAG. This provides us a valuable biomarker for the pain state of an organism," Sullere said.

"This unexplored role of acetylcholine also points towards its potential involvement in the central sensitization processes that contribute to the development of chronic pain conditions. Modifying acetylcholine signaling provides an opportunity to relieve pain and prevent the establishment of the chronic pain state."

Opportunities for new pain-relieving drugs

The results of this work point to multiple opportunities to develop new pain-relieving drugs, either by stimulating the release of acetylcholine or targeting ⍺7 receptors. McGehee said medications targeting these receptors have been tested for multiple diseases, but not yet as painkillers.

"This is a potentially valuable target for new development of analgesics," he said. "We see that inhibiting these cells is important in terms of controlling pain, and it's a very profound mechanism that works beautifully and to a similar degree to what we see with opioids."

More information: Daniel S McGehee, A cholinergic circuit that relieves pain, despite opioid tolerance, Neuron (2023). DOI: 10.1016/j.neuron.2023.08.017. www.cell.com/neuron/fulltext/S0896-6273(23)00627-X

https://medicalxpress.com/news/2023-09-alternative-pain-circuits-brain-relief.html

Potential treatment for nicotine dependence

 New research from the University of Missouri School of Medicine suggests there may be another way to treat cigarette cravings. Researchers found that theta-burst transcranial magnetic stimulation (TBS)—strong, rapidly fluctuating magnetic field pulses that can affect brain activity—can lead to improved self-control, reduced cravings and as a result, less smoking.

People with nicotine dependence tend to have significant structural and functional differences in the brain, compared to healthy non-smokers. Smoking cigarettes has been shown to be associated with less gray matter, which means they have less neurons and other cells in the brain.

Research suggests these differences may affect inhibitory control (IC), which is our control over automatic urges and response to stimuli—what enables humans to stop an impulsive reaction to something.

"Having difficulties with IC may make it harder to avoid smoking when the urge arises, in response to all the cues and contexts in the environment that trigger the behavior to light a cigarette," said lead author Brett Froeliger, Ph.D., professor of Psychiatry.

TBS refers to when magnetic pulses are applied to the brain in bursts of three and come in two forms: continuous TBS (cTBS) and intermittent TBS (iTBS). cTBS consists of applying these three bursts repeatedly for 40 seconds, whereas iTBS applies the same number of pulses irregularly for more than 190 seconds.

Magnetic stimulation has been used to treat other mental illnesses and disorders. cTBS has been experimentally tested to treat generalized anxiety disorder, whereas iTBS to the left dorsolateral prefrontal cortex—a part of your brain responsible for cognitive processes—is FDA-approved for treating major depressive disorder.

The study involved 37 participants, mostly in their late 40's, and examined the effects of both cTBS and iTBS to the right inferior frontal gyrus, a brain region heavily involved with IC. Researchers found that cTBS improved IC, whereas both cTBS and iTBS reduced cravings and, subsequently, smoking.

"Identifying treatments that improve IC may help reduce smoking and can potentially help with preventing relapse following when a person attempts to quit smoking," Froeliger said. "Treatments that improve IC may also help disrupt the cycle of drug use among individuals with other substance use disorders; however, further research is needed to examine the clinical value of TBS for treating substance use disorders."

"Effects of Hyperdirect Pathway Theta-Burst Transcranial Magnetic Stimulation on Inhibitory Control, Craving, and Smoking in Adults with Nicotine Dependence: A Double-Blind Randomized Crossover Trial" was recently published in Biological Psychiatry CNNI.

In addition to Froeliger, study authors include Muaid Ithman, MD, associate professor of clinical psychiatry; MU Ph.D. student Spencer Upton; TBS technician and data analyst Alexander Brown and other researchers from the University of South Carolina and Stanford University. The authors claim no conflicts of interest.

More information: Spencer Upton et al, Effects of Hyperdirect Pathway Theta-Burst Transcranial Magnetic Stimulation on Inhibitory Control, Craving, and Smoking in Adults with Nicotine Dependence: A Double-Blind Randomized Crossover Trial, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging (2023). DOI: 10.1016/j.bpsc.2023.07.014

https://medicalxpress.com/news/2023-09-potential-treatment-nicotine.html

New preclinical system to better turn lab discoveries into effective treatments

 It is an all-too-common fact that potential drugs can look extremely promising in preclinical laboratory testing but fail when it comes to effectively treating humans. To better translate promising lab findings into effective new treatments, a team of researchers from the Keck School of Medicine of USC has developed and tested an innovative new system for conducting preclinical research on six potential new stroke treatments, identifying the strongest candidate for further study.

"We now have a feasible preclinical research system to find promising stroke therapies with a higher chance of success in clinical trials," said Walter J. Koroshetz, MD, director of NIH's National Institute of Neurological Disorders and Stroke (NINDS).

Rather than relying on a single laboratory led by one investigator to test a potential new drug, Patrick D. Lyden, MD, professor of physiology and neuroscience and of neurology at the Keck School of Medicine of USC, coordinated the efforts of a network of laboratories to conduct preclinical research on potential stroke treatments combined with intravascular thrombectomy. A central coordinating body at the Keck School of Medicine developed detailed protocols for the labs to follow to ensure higher levels of scientific rigor than traditional preclinical testing models.

"For years, we have tested drugs on animals first, but we often get it wrong," said Lyden, who is lead author of a study about this network and the research it carried out which was just published in Science Translational Medicine. "Our primary goal with this research was to show there is a better way to do preclinical testing and that this is one way to get better results that can be replicated."

Better models, more rigor

The network, dubbed the Stroke Preclinical Assessment Network, or SPAN, consisted of six laboratories in different locations across the U.S. The team at the Keck School of Medicine was not directly involved in any of the testing. Lyden and his team developed the protocols and procedures the network had to follow; handled the preparation and distribution of the study drugs; collected and analyzed all outcome data; and created a unique system of blinding the testing to prevent bias.

One critical innovation the team instituted, in addition to increasing the number of laboratories involved, was to use animal models that resembled typical stroke patients. Instead of testing drugs mostly on young male mice and rats, as Lyden says is often the case in preclinical research, the researchers also included older mice, mice with diet-induced obesity or hyperglycemia, and rats that were spontaneously hypertensive. The rodents were also evenly split between male and female.

Lyden's team also developed new ways to build more scientific rigor into preclinical testing, standardizing the randomization and blinding practices among the different labs.

All animals in SPAN were logged at USC by the research laboratories using an online database. The animals were randomly assigned to treatment by the USC team and then treated at the appropriate research laboratory. When it came to blinding the study, the team at USC turned all the substances into identical looking powders, assigned them numbers as their only identification and shipped them to the various labs. One of the six treatments involved a medical device that could not be concealed.

"We showed that it is feasible to improve the scientific rigor of preclinical testing and how it can be done," said Lyden. "If research is being done without as much rigor as possible, it is a waste of time, taxpayer money and animal lives."

A possible candidate

The central coordinating team at the Keck School of Medicine also employed a novel statistical method to evaluate the six treatments at four points in the process. While all the substances had been selected for inclusion based on prior research showing promise as a stroke treatment, the USC team analyzed the efficacy of each of the substances at these four points by giving the animals a series of functional tests.

Based on the results of those tests, substances that failed to show sufficient efficacy were dropped. Using this new statistical method, three substances were dropped after the second evaluation, and two more were dropped after the third. Only one substance, uric acid, showed efficacy through all four phases of analysis.

Although uric acid appeared promising in the SPAN trial using the primary endpoint, there were no signs of benefit using the other secondary endpoints. Hence, the SPAN investigators recommend additional animal studies of uric acid before recommending clinical trials in human stroke patients.

"The study acted as we intended it to by sequentially eliminating the futile drugs until we were left with one," said Lyden. "We believe uric acid, based on this evaluation, should be studied further."

More information: Patrick D. Lyden et al, A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.adg8656

https://medicalxpress.com/news/2023-09-team-preclinical-lab-discoveries-effective.html