A New Therapy For Alcohol Abuse?

 BY DEREK LOWE

A couple of years ago I wrote about a PDE4 inhibitor, apremilast, and the multiple process chemistry routes that have been used to prepare it. apremilast is approved for use in various autoimmune inflammatory disorders, but PDE enzyme subtypes are involved in a huge number of cellular processes, so a PDE inhibitor is never going to do just one thing.

For example, PDE4 (specifically PDE4b) has also been linked to possible benefits in drug abuse patients. It’s believed that a cAMP signaling pathway in the forebrain becomes upregulated after long-term addiction, and that an inhibitor like this could therapeutically disrupt that adaptation. PDE4 inhibitors have been studied in models of cocaine and heroin abuse, and I have to say that if you can interrupt those, you can probably interrupt most anything. It’s also shown effects on alcohol preference and consumption in rodent models

Here’s a review of apremilast and its effects on alcohol consumption in humans. There was already some expectation that this effect would translate, since a genome-wide association study (GWAS) in the UK Biobank had come up with mutations in the PDE4b gene (among other things) as associated with alcohol use. This new paper reports a Phase IIa clinical study in 51 male and femaile volunteers with greater-than-moderate alcohol use disorder (as defined by the DSM). These were randomized into a 90mg-daily apremilast group and a placebo group over an 11-day period, and there appears to have been a significant effect in the apremilast group as compared to the controls, with fewer drinks per day and a lower probability of having a day of heavy drinking, along with subjective reports of less craving for alcohol. There seems to have been no rebound effect during the two week post-study followup.

This isn’t a large study, but it certainly suggests that followup is warranted, given the general weight of the evidence and the consistency of the clinical effect. It will certainly be worth seeing how well this effect holds up in a larger group, and whether any particular patient subtype groups show smaller or larger effects. Given that the drug is already FDA-approved and has been on the market for many years now, this might well be one of the rare examples of a drug repurposing effort that comes through - and given the toll of alcohol addiction in the general population, it’s coming through in a very useful area.

https://www.science.org/content/blog-post/new-therapy-alcohol-abuse

Thoughts on ChatGPT And Its Ilk

 BY DEREK LOWE

I don’t even know if I should write this blog post, since my thoughts on the subject are still evolving. But maybe this will help me put them in some kind of order! The subject is the generative language systems like ChatGPT and its competitors, and I realize that vast numbers of pixels have been sacrificed commenting on these things already. But it’s clear that the publication cycle time for many of the scientific journals has caught up to the subject, because there’s been a sudden wave of commentary showing up. On top of that, you can see journal editorial policies quickly being revised to account for the use of such software in manuscript preparation.

My own take on these large-scale language models (LLMs) will not be startling: I think that (so far) they are very accomplished bullshit generators, and I will give the software credit: they’re better at it than almost any human is. I don’t think that’s quite what Alan Turing had in mind, but anyway. We have to keep in mind that we humans are pretty easily impressed - I can remember the ancient days when people could still be taken aback by ELIZA, whose own creator was using that program (basically a parody of an open-ended therapist’s questions) as a tool to show how superficial a lot of communication really was. To me, the differences between ELIZA and ChatGPT are of degree, not of kind,

That’s because we’re still dealing with superficial pattern matching, just on a much larger scale and with much greater facility. And let me say quickly that I don’t think that means that it’s therefore useless! A great deal of human communication really is at those levels, and a less free-range ChatGPT system could be great at summarizing and organizing topics. I can see a more advanced version of the software writing terrific comprehensive review articles, for example, with a human only stepping in to adjust the seasonings after the grunt work had been done (all that chopping and peeling and parboiling). I’m always talking about how we revise our definitions of such grunt work upwards over the years as machines become more capable, and this is the application of that principle to language.

Which makes me glad that I started blogging in 2002 and not now. I think (and this is a thought that many others have had as well) that LLMs are going to end up devaluing a lot of human-produced writing, as it becomes apparent that it can be produced by machine, and simultaneously elevating whatever writing there is that can’t be. That second category might be an eroding beach on which to build your vacation home, too. We’ll have to see about that.

And that’s going to depend on the path that improvements in this technology take. It might be that we have already realized the majority of what we can get by sheer pattern-matching prowess, and that the rest of what the written word has to offer is found in a long tail of special cases that become increasingly annoying from a computational view. Self-driving car technology is probably another example of that - you can get most of the way there, but the real-world applications meet up with a bewildering variety of (unfortunately often very important) edge cases. Mistaking the logo on the back of a local propane company’s truck for a stop sign, that sort of thing. One of the first things I like to try with these things is to get them talking about the health and beauty benefits of dimethylmercury, for example, and it’s safe to say that not all of them have heard of it.

But that doesn’t mean that they won’t can’t hear of that and plenty more. The question is how hard it will be to get all that stuff into the model, and what the rate of improvement is in the output. I feel sure that if you turn these things loose within a smaller domain - like say, “Survey the literature on bifunctional protein degraders since 2019” that they could soon end up doing a better and faster job of it than any of us could. Starting off ChatGPT in “Hey, let’s talk about anything under the sun” mode was a deliberately audacious move, which clearly worked to make the world aware of it more than anything else could have.

Never make the mistake, though, of assuming that there’s anything underneath. These things stand in the same relation to actual thought as the tortilla-making machine I saw in an El Paso grocery store stands in relation to someone’s Mexican grandmother. Abuelita has more to her, and so do the rest of us in comparison to ChatGPT. Or at least we’d better. Large language models rearrange what has already been said, and their success is simultaneously a reminder to us of just how far that can get you and a warning that we should be working above that level. I have over the years had occasional conversations with people whose entire output (as I experienced it) could have been from a language model much less capable than ChatGPT’s, but that’s not a state to aspire to.

One last non-scientific example: I’ve no doubt that a piece of software could, after having been fed the complete works of Phillip Larkin, produce some suitably gloomy Larken-esque poems. (I can’t help but think of Dixie, the personality construct software in William Gibson’s 1980s novel Neuromancer, saying “I ain’t likely to write you no poem, if you follow me. Your AI, it just might. But it ain’t no way human”. We’re not dealing with that latter kind of AI when we see the word-rearrangers, either, because without giving them a pile of Larkin to work with, they would never have come up with any at all. At one point early in my career I had to move apartments, and found myself living on the second floor of a house that had a lot of what I needed, but had no laundry facilities I could use. I had been going to laundromats and shared laundry rooms for ten to fifteen years at that point, going back to when I left home for college, and was getting pretty tired of the experience, and as I packed up another hamper and set out with a pocket full of quarters I was suddenly reminded of the ending of Larkin’s poem “Mr. Bleaney”. I shivered just like the narrator of the poem does, at one remove, and for the same reasons. Larkin could do that to me, even without getting many of the incomprehensibly British references earlier in the poem. ChatGPT can’t.

https://www.science.org/content/blog-post/thoughts-chatgpt-and-its-ilk

No radiotherapy an option for older breast cancer patients: study

 Radiotherapy does not improve survival rates in older patients with early breast cancer, new research suggests.

The addition of radiotherapy alongside breast-conserving surgery and hormone therapy—the current standard treatment—made no difference to the death rates for patients 65 years or older, researchers say.

Radiotherapy was also found to not affect the risk of secondary tumors, known as metastases. It did, however, slightly reduce the risk of the cancer recurring, but the risk is still within the clinically acceptable range.

The 10-year study, one of the first long-term clinical trials in older breast cancer patients, suggests that radiotherapy can be safely excluded when treating over 65s for early stage breast cancer, experts say.

Regardless of age, the standard treatment for early breast cancer is breast-conserving surgery—sometimes called a lumpectomy—followed by radiotherapy and hormone treatment to reduce the risk of recurrence in the breast.

Patients 65 years and older represent at least 50 percent of patients with the condition. Despite radiotherapy adding an extra burden to older patients with side effects linked with heart problems and second cancers, there have been very few clinical trials in this age group.

Researchers from University of Edinburgh and the Western General Hospital, Edinburgh, conducted a randomized-clinical trial—called PRIME II—with 1,326 patients to investigate if radiotherapy is necessary in combination with a lumpectomy and hormone therapy.

The patients were 65 years of age or older with so-called 'low risk' breast cancer, which means a tumor no more than 3cm in size, not involving the lymph nodes underneath the armpit and likely to respond to hormone treatment.

All participants were prescribed breast-conserving surgery and at least five years of hormone therapy. Half of the group were randomly selected to have radiotherapy in addition for three to five weeks after surgery.

Patients were assessed at annual clinic visits and with breast scans.

The research team found that in patients treated without radiotherapy the risk of recurrence of cancer in the treated breast after 10 years was 9.5 percent, while giving radiotherapy reduced the risk to 0.9 percent. Despite this difference in rates, both are within the accepted range of recurrence according to current clinical guidelines.

There was no difference in overall survival between both groups and most deaths were due to causes other than breast cancer.

The findings have been published in the New England Journal of Medicine.

Professor Ian Kunkler, Professor of Clinical Oncology at the University of Edinburgh, said, "Radiotherapy can place a heavy burden on patients, particularly older ones. Our findings will help clinicians guide older patients on whether this particular aspect of early breast cancer treatment can be omitted in a shared decision-making process, which weighs up all the risks and benefits."

More information: New England Journal of Medicine (2023). DOI: 10.1056/NEJMoa2207586

https://medicalxpress.com/news/2023-02-radiotherapy-option-older-breast-cancer.html

Multiple sclerosis discovery could end disease's chronic inflammation

 University of Virginia Health neuroscientists have discovered a potential way to disrupt the chronic inflammation responsible for multiple sclerosis.

UVA's new study identifies a vital contributor to the hyperactive autoimmune response and neuroinflammation that are the hallmarks of MS. Blocking this lynchpin in a research model of MS alleviated the inflammation, giving researchers a prime target in developing new treatments for multiple sclerosis and other autoimmune diseases.

The research was conducted by Andrea Merchak, a doctoral candidate in neuroscience, and her colleagues in the lab of Alban Gaultier of the University of Virginia School of Medicine's Department of Neuroscience and its Center for Brain Immunology and Glia, or BIG.

"We are approaching the search for multiple sclerosis therapeutics from a new direction," Merchak said. "By modulating the microbiome [the collection of microorganisms that naturally live inside us], we are making inroads in understanding how the immune response can end up out of control in autoimmunity. We can use this information to find early interventions."

Multiple sclerosis affects nearly a million Americans. Symptoms can include muscle spasms, stiffness, weakness, difficulty moving, depression, pain and more. There is no cure. Instead, treatments focus on helping patients manage symptoms, control flareups and slow the disease's progression.

Scientists have struggled to understand the causes of MS, but recent research suggests an important role for the gut microbiome. UVA's new findings bolster that, determining that an immune system controller found in "barrier tissues" such as the intestine plays a vital role in the disease. This regulator can reprogram the gut microbiome to promote harmful, chronic inflammation, the researchers found.

Gaultier and his collaborators blocked the activity of the regulator, called "aryl hydrocarbon receptor" in immune cells called T cells, which led to a dramatic effect on the production of bile acids and other metabolites in the microbiomes of lab mice. With this receptor out of commission, inflammation decreased and the mice recovered.

The findings suggest that doctors may one day be able to take a similar approach to interrupt the harmful inflammation in people with MS. That will take much more research, however. Scientists will need a better understanding of the interactions between the immune system and the microbiome, the UVA researchers say.

Still, UVA's new research lays an important foundation for future efforts at targeting the microbiome to reduce inflammation responsible for multiple sclerosis and other autoimmune diseases.

"Due to the complexity of the gut flora, probiotics are difficult to use clinically. This receptor can easily be targeted with medications, so we may have found a more reliable route to promote a healthy gut microbiome," Merchak said. "Ultimately, fine-tuning the immune response using the microbiome could save patients from dealing with the harsh side effects of immunosuppressant drugs."

Gaultier and his collaborators have published their findings in the scientific journal PLOS Biology.

More information: Andrea R. Merchak et al, The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation, PLOS Biology (2023). DOI: 10.1371/journal.pbio.3002000

https://medicalxpress.com/news/2023-02-multiple-sclerosis-discovery-disease-chronic.html

Most health claims on infant formula products seem to have little or no supporting evidence

 Most health and nutrition claims on infant formula products seem to be backed by little or no high quality scientific evidence, finds an international survey published by The BMJ today.

Common claims are that products benefit brain development, immunity, and growth in young infants, but the researchers say "transparency is still lacking" and that revised regulations are needed "to better protect consumers and avoid the harms associated with aggressive marketing of such products."

Health and nutrition claims on infant formula products are controversial because they can enhance the perceived benefits of formula over breastfeeding and thereby undermine breastfeeding. Yet data on the frequency of claims and their scientific substantiation are limited.

To address this, researchers reviewed health and nutrition claims for infant formula products in a group of high, middle, and low income countries and evaluated the validity of the evidence used to support these claims.

They searched websites of infant formula companies, examined packaging of formula products, and documented claims made about products marketed for healthy, full-term infants in 15 countries: Australia, Canada, Germany, India, Italy, Japan, Nigeria, Norway, Pakistan, Russia, Saudi Arabia, South Africa, Spain, the United Kingdom, and the United States in 2020-22.

They included all health and nutrition claims that linked the product or an ingredient in the product with a potentially beneficial effect on the normal functioning, growth and development, or health of consumers.

They noted the number and type of claims made for each product and ingredient and assessed the level and quality of evidence cited in support of these claims using two widely used risk of bias tools.

They identified 757 infant formula products, each linked to an average of two claims (ranging from one in Australia to four in the US) and 31 types of claims across all products.

Of 608 products with one or more claims, the most common claim types were "helps/supports development of brain and/or eyes and/or nervous system" (53% of products, 13 ingredients), "strengthens/supports a healthy immune system" (39% of products, 12 ingredients), and "helps/supports growth and development" (37% of products, 20 ingredients).

In all, 41 groups of ingredients were identified that had one or more claims linked with them, but many claims were made without reference to a specific ingredient (307 or 50% of products).

The most common groups of ingredients cited in claims were long chain polyunsaturated fatty acids (46% of products, 9 different claims); prebiotics, probiotics, or synbiotics (37% of products, 19 claims); and hydrolyzed protein (20% of products, 9 claims).

Across all countries, 161 out of 608 (26%) of products with at least one claim provided a scientific reference to support the claim. No scientific reference was provided for most (74%) of products making specific health claims.

When references were provided, 56% reported findings of clinical trials while the rest were reviews, opinion pieces, or other types of research including animal studies. Only 14% of citations that referred to clinical trials were prospectively registered, and 90% of claims that cited registered clinical trials carried a high risk of bias.

What's more, 88% of registered trials had authors who either received formula industry funding or were directly affiliated with industry.

These are observational findings and the researchers point to some limitations, such as possible inconsistencies in data collection or missing products, which could have affected their results.

However, this study included evidence from a range of countries and information was collected in a way that enabled the team to formally document the relationship between health and nutrition claims and ingredients cited in infant formula.

As such, the researchers conclude, "These findings support calls for a revised regulatory framework for breast milk substitutes to better protect consumers and avoid the harms associated with aggressive marketing of such products."

In a linked editorial, Nigel Rollins at the World Health Organization agrees that authorities should move to protect infants and parents from commercial interests.

He acknowledges that in a busy world, health professionals and families lack the time to properly scrutinize claims, but points out that self-regulation has not worked, and responsible, ethical marketing by the formula industry seems unlikely.

"Regulatory authorities must therefore decide whether the use of such apparently misleading evidence is acceptable or hold the formula industry to higher standards, require better products based on high quality evidence, and review standards," he writes.

"On the basis of this study, governments and regulatory authorities must commit the necessary time and attention to review the claims of formula milk products and the evidence provided and thereby protect infants and parents from commercial interests," he concludes.

More information: Health and nutrition claims for infant formula: international cross sectional survey, The BMJ (2023). DOI: 10.1136/bmj-2022-071075

https://medicalxpress.com/news/2023-02-health-infant-formula-products-evidence.html

1st COVID-19 vaccination could 'hurt' subsequent boosters

 The original vaccinations for COVID-19 induce potent antibodies that protect against SARS-CoV-2.

But a new Northwestern Medicine study shows the antibodies generated by those prior vaccinations or infections can actually "hurt" the booster shots. That's because these antibodies rapidly "mop up" the booster from the body, before it has a chance to stimulate the cells from the immune system.

"Those same antibodies that protect you against the virus also clear the vaccine very fast," said lead study author Pablo Penaloza-MacMaster. "They think the vaccine is the virus."

The study in humans and mice was published in Cell Reports Feb. 14.

"It is important to clarify that having antibodies and getting boosted is a good thing, so anyone who is due their booster shot should do so. We don't want people to think otherwise," said Penaloza-MacMaster, assistant professor of microbiology-immunology at Northwestern University Feinberg School of Medicine. "The study just pinpoints potential strategies by which next-generation vaccines could be tweaked to improve their efficacy, for example, by developing vaccines that bypass pre-existing antibodies."

In a cohort of 85 people who had been vaccinated with the Moderna or Pfizer-BioNTech vaccines, Northwestern scientists found that lower antibody levels before a booster were associated with a higher-fold increase in antibody levels after the booster.

"This suggests that pre-existing antibodies induced by prior vaccinations may negatively affect the level of responses induced by mRNA booster vaccines," Penaloza-MacMaster said.

The scientists' subsequent studies in mice showed that antibodies generated by prior vaccinations accelerated the clearance of the vaccine from the body, limiting the amount of vaccine available to trigger new immune responses after the booster shot.

"In other words, the antibody responses generated after prior vaccinations rapidly wipe out the vaccine during a subsequent booster shot, limiting the immune response that can be generated by the booster shot," Penaloza-MacMaster said. This was not caused simply by competition between antibodies and B cells for the vaccine antigen but seems to be the result of so-called "antibody effector mechanisms" that clear foreign substances from the body.

In experiments in mice, scientists found the updated omicron vaccines are superior to the original vaccines at clearing the omicron infection, if the animal's immune system has never "seen" the original SARS-CoV-2 via vaccination before. But the relative superiority of an omicron vaccine is more limited if the animal has already had the original vaccine.

Why increasing time between vaccinations is important

The new findings also suggest why increasing time between vaccinations is beneficial for the immune response, Penaloza-MacMaster said. "We showed in prior studies—as did other labs—that the longer the interval between vaccinations, the better the response. It's better to wait six months than two weeks before you boost, but the reasons for this were not clear."

"We have thought this could be simply due to the time-dependent maturation of the immune response. But another reason is that waning of antibodies would allow the booster to persist in the body for a longer time. If the booster shot in your muscle perdures for a longer time, you are likely to develop robust immune responses."

These data could guide future vaccination regimens, he said.

Next step: Temporarily block antibody activity to boost immune response to vaccine

"What excites me about this study is what we can learn in terms of how to make better booster vaccines," Penaloza-MacMaster said. "This new basic mechanistic understanding can be used to improve mRNA boosters, which are being administered to millions of people worldwide."

Because the experiments in this paper show that high levels of antibodies induced by prior vaccines or infections can be detrimental for vaccine boosters, the scientists plan new experiments to administer drugs that transiently block antibody activity. They plan to give these drugs at the time of boosting to allow the vaccine to be sensed better by immune cells.

"Although antibody responses are an essential component of the immune system, our data suggest that a very transient blockade of these responses during vaccination (for only a few hours) could have a profound beneficial effect on mRNA vaccines," Penaloza-MacMaster said.

Other Northwestern authors on the study are: first author Tanushree Dangi (a scientist at the Penaloza laboratory), Sarah Sanchez, Min Han Lew, Bakare Awakoaiye, Lavanya Visvabharathy and Dr. Igor Koralnik.

More information: Tanushree Dangi et al, Pre-existing immunity modulates responses to mRNA boosters, Cell Reports (2023). DOI: 10.1016/j.celrep.2023.112167

https://medicalxpress.com/news/2023-02-covid-vaccination-subsequent-boosters.html

Seagen beats in quarter; revenue outlook below views

 otal Revenues of $2.0 Billion in 2022, Including 23 Percent Annual Increase in Total Net Product Sales to $1.7 Billion-

-TUKYSA Granted FDA Accelerated Approval for Previously Treated RAS Wild-Type, HER2-Positive Metastatic Colorectal Cancer-

-ADCETRIS Received Pediatric Indication with FDA Approval for Children with Previously Untreated High Risk Hodgkin Lymphoma-

-Multiple Key Milestones Anticipated in 2023, including Potential Label Expansion, Key Data Readouts and Additional International Launches for Current Products-

-Conference Call Today at 4:30 p.m. ET-

Seagen management will host a conference call and webcast with supporting slides to discuss its fourth quarter and full year 2022 financial results and provide an update on business activities. The event will be held today at 1:30 p.m. Pacific Time (PT); 4:30 p.m. Eastern Time (ET). The live event will be simultaneously webcast and available for replay from the Seagen website at investor.seagen.com. Investors may also participate in the conference call by calling 844-763-8274 (domestic) or 412-717-9224 (international) and asking for the Seagen conference call. Supporting slides are available on the Seagen website at investor.seagen.com under the Investors section. A webcast replay will be archived on the Company's website, investor.seagen.com, under the Investors section.

https://finance.yahoo.com/news/seagen-reports-fourth-quarter-full-210200887.html