Features that may make motor neurons vulnerable to ALS

 New research offers clues about the biology of cells in the spinal cord that die off in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. A team of researchers supported by the National Institutes of Health has found evidence linking motor neurons' large cell size and supporting structure with the genes that underlie their vulnerability to degeneration in ALS. Findings appeared in Neuron.

The study resulted in a catalog (or "atlas") characterizing the diverse community of cell types within the human spinal cord. By examining gene expression at the single-cell level, the researchers identified dozens of cell types in the spinal cord and analyzed their molecular profiles.

They demonstrated the usefulness of the atlas by looking closely at motor neurons, which provide voluntary movement and motor control. Motor neurons, which degenerate and die in ALS, are large cells with one long extension called an axon―up to a meter long―that conducts signals from the spinal cord to the muscle fiber.

The team found that motor neurons are distinguished by a set of genes that may enable the large size of the motor neuron cell body and lengthy axon, but also underlie their vulnerability to degeneration. Their molecular profile was defined by genes involved in cytoskeletal structure, which gives the cell shape and organizes the structures within; neurofilament genes related to cell size; and genes linked to the onset of ALS.

Additional experiments showed that ALS-related genes are also enriched in motor neurons in mice. With these findings taken together, the study gives insight into ALS and demonstrates the utility of the spinal cell atlas for studying disease and possible interventions.

More information: Archana Yadav et al, A cellular taxonomy of the adult human spinal cord, Neuron (2023). DOI: 10.1016/j.neuron.2023.01.007

https://medicalxpress.com/news/2023-02-features-motor-neurons-vulnerable-als.html

Why lung cancer doesn't respond well to immunotherapy

 Immunotherapy—drug treatment that stimulates the immune system to attack tumors—works well against some types of cancer, but it has shown mixed success against lung cancer.

A new study from MIT helps to shed light on why the immune system mounts such a lackluster response to lung cancer, even after treatment with immunotherapy drugs. In a study of mice, the researchers found that bacteria naturally found in the lungs help to create an environment that suppresses T-cell activation in the lymph nodes near the lungs.

The researchers did not find that kind of immune-suppressive environment in lymph nodes near tumors growing near the skin of mice. They hope that their findings could help lead to the development of new ways to rev up the immune response to lung tumors.

MIT graduate student Maria Zagorulya is the lead author of the paper, which appears today in the journal Immunity.

"There is a functional difference between the T-cell responses that are mounted in the different lymph nodes. We're hoping to identify a way to counteract that suppressive response, so that we can reactivate the lung-tumor-targeting T cells," says Stefani Spranger, the Howard S. and Linda B. Stern Career Development Assistant Professor of Biology, a member of MIT's Koch Institute for Integrative Cancer Research, and the senior author of the new study.

Credit: Immunity (2023). DOI: 10.1016/j.immuni.2023.01.010 A new MIT study explains why dendritic cells (green) in lymph nodes that drain from the lungs fail to stimulate killer T cells (white) to attack lung tumors. Credit: Massachusetts Institute of Technology

Failure to attack

For many years, scientists have known that cancer cells can send out immunosuppressive signals, which leads to a phenomenon known as T-cell exhaustion. The goal of cancer immunotherapy is to rejuvenate those T cells so they can begin attacking tumors again.

One type of drug commonly used for immunotherapy involves checkpoint inhibitors, which remove the brakes on exhausted T cells and help reactivate them. This approach has worked well with cancers such as melanoma, but not as well with lung cancer.

Spranger's recent work has offered one possible explanation for this: She found that some T cells stop working even before they reach a tumor, because of a failure to become activated early in their development. In a 2021 paper, she identified populations of dysfunctional T cells that can be distinguished from normal T cells by a pattern of gene expression that prevents them from attacking cancer cells when they enter a tumor.

"Despite the fact that these T cells are proliferating, and they're infiltrating the tumor, they were never licensed to kill," Spranger says.

In the new study, her team delved further into this activation failure, which occurs in the lymph nodes, which filter fluids that drain from nearby tissues. The lymph nodes are where "killer T cells" encounter dendritic cells, which present antigens (tumor proteins) and help to activate the T cells.

To explore why some killer T cells fail to be properly activated, Spranger's team studied mice that had tumors implanted either in the lungs or in the flank. All of the tumors were genetically identical.

The researchers found that T cells in lymph nodes that drain from the lung tumors did encounter dendritic cells and recognize the tumor antigens displayed by those cells. However, these T cells failed to become fully activated, as a result of inhibition by another population of T cells called regulatory T cells.

These regulatory T cells became strongly activated in lymph nodes that drain from the lungs, but not in lymph nodes near tumors located in the flank, the researchers found. Regulatory T cells are normally responsible for making sure that the immune system doesn't attack the body's own cells. However, the researchers found that these T cells also interfere with dendritic cells' ability to activate killer T cells that target lung tumors.

The researchers also discovered how these regulatory T cells suppress dendritic cells: by removing stimulatory proteins from the surface of dendritic cells, which prevents them from being able to turn on killer-T-cell activity.

Microbial influence

Further studies revealed that the activation of regulatory T cells is driven by high levels of interferon gamma in the lymph nodes that drain from the lungs. This signaling molecule is produced in response to the presence of commensal bacterial—bacteria that normally live in the lungs without causing infection.

The researchers have not yet identified the types of bacteria that induce this response or the cells that produce the interferon gamma, but they showed that when they treated mice with an antibody that blocks interferon gamma, they could restore killer T cells' activity.

Interferon gamma has a variety of effects on immune signaling, and blocking it can dampen the overall immune response against a tumor, so using it to stimulate killer T cells would not be a good strategy to use in patients, Spranger says. Her lab is now exploring other ways to help stimulate the killer T cell response, such as inhibiting the regulatory T cells that suppress the killer-T-cell response or blocking the signals from the commensal bacteria, once the researchers identify them.

More information: Maria Zagorulya et al, Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer, Immunity (2023). DOI: 10.1016/j.immuni.2023.01.010

https://medicalxpress.com/news/2023-02-lung-cancer-doesnt-immunotherapy.html

Ohio Man Who Identifies As Female Faces Charges For Being Naked In Locker With Young Girls Present

 by Mimi Nguyen Ly via The Epoch Times,

A man who identifies as a female has been charged with public indecency for allegedly being naked while in the presence of young girls, in the women’s locker room of a YMCA in Ohio.

The man, Darren C. Glines, 31, of Fairborn, was charged with three counts of indecent exposure for three separate incidents spanning 2021–2022 that were reported by three different people.

Glines has not had gender reassignment surgery. He identifies as transgender and uses the name Rachel, local station WHIO reported.

Under Ohio law, public indecency is a misdemeanor of the fourth degree.

The three incidents occurred on Sept. 26, 2021, Nov. 7, 2022, and between Nov. 30, 2021, and Nov. 30, 2022, according to the complaint (pdf) obtained by the Daily Caller.

In the third incident, the person who filed the complaint reported that “at least three female juveniles were present when the naked man was in their vicinity.”

Glines “was identified by the reporting persons and the Xenia police were able to identify the identification via their investigation,” according to the court document.

The president of the Xenia City Council, Williams Urshcel, shared at a recent public gathering that one of the women that complained was told by the front desk at the YMCA facility that Glines “is actually a woman, and that you shouldn’t be disturbed by this.”

But a spokesperson for the city said Urshel’s comments were not authorized by or on behalf of the rest of the City Council, the city mayor, the city manager, and the law director.

The city’s law department doesn’t plan to bring charges against the YMCA over the matter, the spokesperson added.

The YMCA of Greater Dayton told WHIO in a statement that it will comply with legal mandates but also continue to protect the privacy and safety of its members.

“Under no circumstance will we investigate an individual’s birth identity and then assign individuals to locker rooms,” the statement reads.

“That would be counter to the law, counter to respect for all people and it is not who or what we are as an organization.”

The YMCA of Greater Dayton told Dayton Daily News that non-discrimination laws in Ohio allow people to use facilities that align with their gender identity.

It added that locker room guidelines in its facilities ask people to “remain properly covered while in public areas of the locker room.”

https://www.zerohedge.com/medical/ohio-man-who-identifies-female-faces-charges-being-naked-locker-room-while-young-girls-were

Magenta Therapeutics to Explore Strategic Alternatives

 Magenta Therapeutics (Nasdaq: MGTA), a clinical-stage biotechnology company focused on improving stem cell transplantation, today announced that it has completed a review of its business, including the status of its programs, resources, and capabilities. Magenta has made the determination to halt further development of its programs and conduct a comprehensive review of strategic alternatives focused on maximizing shareholder value.

As part of this review process, Magenta will explore potential strategic alternatives that may include, but are not limited to, an acquisition, merger, business combination, or other transaction. There can be no assurance that this review process will result in Magenta pursuing a transaction or that any transaction, if pursued, will be completed on attractive terms. Magenta has not set a timetable for completion of this review process and does not intend to comment further unless or until the Board of Directors has approved a definitive course of action, the review process is concluded, or it is determined that other disclosure is appropriate.

https://finance.yahoo.com/news/magenta-therapeutics-explore-strategic-alternatives-210500832.html

Munger: Why America should ban crypto

 In the U.S. in recent years, privately owned companies have issued thousands of new cryptocurrencies, large and small. These have later become publicly traded without any governmental pre-approval of disclosures.

In some cases, a big block of cryptocurrency has been sold to a promoter for almost nothing, after which the public buys in at much higher prices without fully understanding the pre-dilution in favor of the promoter.

All this wild and wooly capitalism is much like that described in a remark often attributed to Mark Twain, who was thought to have said that "a mine is a hole in the ground with a liar on top."

Celebrities have been accused of promoting cryptocurrencies for their own benefit.

Such wretched excess has gone on because there is a gap in regulation. A cryptocurrency is not a currency, not a commodity, and not a security. Instead, it’s a gambling contract with a nearly 100% edge for the house, entered into in a country where gambling contracts are traditionally regulated only by states that compete in laxity. Obviously the U.S. should now enact a new federal law that prevents this from happening.

Two interesting precedents may guide us into sound action. In the first precedent, the communist government of China recently banned cryptocurrencies because it wisely concluded that they would provide more harm than benefit. And, in the second precedent, from the early 1700s, England reacted to a horrible depression that followed the blow up of a promotional plan to get vast profits by using slow-moving sailing ships to trade with very poor people halfway around the world.

Charlie Munger, vice chairman of Berkshire Hathaway Inc., speaks during the Daily Journal Corp. shareholder meeting in Los Angeles, California, U.S., on Thursday, Feb. 14, 2019. Munger discussed investing, banks, China, and health care at the meeting (Patrick T. Fallon/Bloomberg / Getty Images)

What the English Parliament did in its anguish when this crazy promotion blew up, was direct and simple: It banned all public trading in new common stocks and kept this ban in place for about 100 years. And, in that 100 years, England made by far the biggest national contribution to the march of civilization as it led strongly in both the Enlightenment and the Industrial Revolution and, to boot, spawned off a promising little country called the United States.

What should the U.S. do after a ban of cryptocurrencies is in place? Well, one more action might make sense: Thank the Chinese communist leader for his splendid example of uncommon sense.

Mr. Munger is vice chairman of Berkshire Hathaway.

https://www.foxbusiness.com/money/america-should-ban-crypto

Cardiorenal disease biotech Mineralys Therapeutics sets terms for $150 million IPO

 Mineralys Therapeutics, a Phase 2 biotech developing an in-licensed therapy for cardiorenal disorders, announced terms for its IPO on Thursday.

The Radnor, PA-based company plans to raise $150 million by offering 10 million shares at a price range of $14 to $16. At the midpoint of the proposed range, Mineralys Therapeutics would command a fully diluted market value of $574 million.

Mineralys is developing medicines to target diseases driven by abnormally elevated aldosterone, focused on cardiorenal disorders. Its sole candidate, lorundrostat, is a proprietary, orally administered, highly selective aldosterone synthase inhibitor (ASI) licensed from Mitsubishi Tanabe that is initially being developed for uncontrolled hypertension. The company completed a Phase 2 proof-of-concept trial of lorundrostat for uncontrolled hypertension and resistant hypertension in 2022 and plans to initiate a randomized, double-blind, placebo-controlled Phase 2 trial in the 1H23, followed by a Phase 3 trial in the 2H23.

Mineralys Therapeutics was founded in 2019 and plans to list on the Nasdaq under the symbol MLYS. BofA Securities, Evercore ISI, Stifel, Guggenheim Securities, Credit Suisse, and Wells Fargo Securities are the joint bookrunners on the deal. It is expected to price during the week of February 6, 2023.

Relevant Profile: MLYS   

https://www.renaissancecapital.com/IPO-Center/News/97225/Cardiorenal-disease-biotech-Mineralys-Therapeutics-sets-terms-for-$150-mill

Wither CBD?

 Anyone who’s been paying attention to the FDA’s evolving thinking on cannabidiol (a derivative of cannabis also known as CBD) shouldn’t have been at all surprised at the agency’s January 26, 2023 announcement that there are too many unknowns about CBD products to regulate them as foods or supplements under the agency’s current structure and called on Congress to create new rules for the massive and growing market. And, specifically, per FDA Deputy Commissioner (and Chair of the agency’s CBD working group) Dr. Janet Woodcock, “We have not found adequate evidence to determine how much CBD can be consumed, and for how long, before causing harm.”

This is entirely consistent with what the FDA said in its pre-pandemic March 2020 missive “FDA Advances Work Related to Cannabidiol Products with Focus on Protecting Public Health, Providing Market Clarity.” It was an unambiguous regulatory finger-wagging at an exuberant but still-nascent industry that still just doesn’t get it. Alas, a lot of bad science doesn’t equal even a little good science.

he 2020 FDA statement begins, “Over the past year, the U.S. Food and Drug Administration has embarked on a comprehensive evaluation of cannabidiol (CBD) products, with a focus on educating the public about the risks and unknowns of these products, gathering the science needed to better understand both these safety concerns and potential benefits to inform our regulatory approach, as well as taking steps when necessary to address products that violate the law in ways that raise a variety of public health concerns.”

Translation: There’s no good science and we’re going to start writing enforcement letters. And they have. Too many for some, too few for others.

The agency continues, “Today, we are providing updates on our efforts in this area, including several new steps in areas of education, research, and enforcement with the ultimate goal of continuing to protect the public health and working to provide market clarity.”

Translation: It’s going to be a slow process and we’re obviously going to have to help you. Ignore the need for real science at your own peril. Oh, and about those claims, “… we are concerned that some people wrongly think that the myriad of CBD products on the market have been evaluated by the FDA and determined to be safe, or that using CBD ‘can’t hurt.’ Aside from one prescription drug approved to treat two rare, severe pediatric epilepsy disorders, no other CBD products have been evaluated or approved by the FDA.”

Safety issues? “There may be risks that need to be considered before using CBD products outside of the monitored setting of a prescription from your health care provider.”

Translation: We think there may very well be safety issues such as:

“… potential liver injury, interactions with other drugs and male reproductive toxicity, as well as side effects such as drowsiness. In addition, there is still much we do not know about other potential risks. For example, other than the approved prescription drug, we know little about the potential effects of sustained and/or cumulative use of CBD, co-administration with other medicines, or the risks to vulnerable populations like children, pregnant and lactating women, the elderly, unborn children, and certain animal populations. This does not mean that we know CBD is unsafe …”

Translation: But we have our suspicions.

“To address the questions and concerns we’ve already raised, we’re seeking reliable and high-quality data.”

Translation: We don’t have it because it doesn’t exist.

“This includes data on, among other things: the sedative effects of CBD; the impacts of long-term sustained or cumulative exposure to CBD; transdermal penetration and pharmacokinetics of CBD; the effect of different routes of CBD administration (e.g., oral, topical, inhaled) on its safety profile; the safety of CBD for use in pets and food-producing animals; and the processes by which “full spectrum” and “broad spectrum” hemp extracts are derived, what the content of such extracts is, and how these products may compare to CBD isolate products.”

Translation: It’s time for the proponents of CBD, including many highly vocal patients, physicians, pharmacists, manufacturers, and distributors, to become part of the solution.

“Given the importance of answering these questions, we’re exploring a number of ways to address the data gaps as quickly as possible. This includes encouraging, facilitating, and initiating more research on CBD, providing venues for industry and researchers to share new data with the agency and identifying opportunities to further collaborate with our federal partners at Centers for Disease Control and Prevention, Substance Abuse and Mental Health Services Administration and National Institute on Drug Abuse on this important issue.”

Translation: It’s a complicated issue that extends beyond the exclusive boundaries of the FDA – or of existing FDA authorities.

In March 2020, the FDA predicted a long and winding road.

“In the coming days, we are re-opening the public docket we established for our May 2019 public hearing. The docket provides a valuable conduit for submission of scientific data on CBD to the agency, so we have decided to extend the comment period indefinitely to allow the public to comment and to share relevant data with the agency. As the agency continues to move forward to explore viable pathways for CBD products outside the drug context, this extension will allow stakeholders to continue to provide relevant data as research in this area evolves.”

Translation: Key word, “indefinitely.”

And in conclusion: “We recognize the significant public interest in CBD, and we must work together with stakeholders and industry to develop high-quality data to close the substantial knowledge gaps about the science, safety, and quality of many of these products. We are committed to working efficiently to further clarify our regulatory approach to these products – as always, using science as our guide and upholding our rigorous public health standards.”

Nearly three years later, Dr. Woodcock has issued an honest and consistent statement: “The FDA will continue to take action against CBD and other cannabis-derived products to protect the public, in coordination with state regulatory partners, when appropriate. We will remain diligent in monitoring the marketplace, identifying products that pose risks and acting within our authorities. The FDA looks forward to working with Congress to develop a cross-agency strategy for the regulation of these products to protect the public’s health and safety.

Keep calm and carry on.

Peter J. Pitts, a former FDA Associate Commissioner, is President of the Center for Medicine in the Public Interest and a Visiting Professor at the University of Paris School of Medicine.

https://www.realclearhealth.com/articles/2023/01/31/wither_cbd_111456.html