Reversing chemotherapy resistance in pancreatic cancer

 Pancreatic cancer is a particularly aggressive and difficult-to-treat cancer, in part because it is often resistant to chemotherapy. Now, researchers at Stanford have revealed that this resistance is related to both the physical stiffness of the tissue around the cancerous cells and the chemical makeup of that tissue. Their work, published on July 4 in Nature Materials, shows that this resistance can be reversed and reveals potential targets for new pancreatic cancer treatments.

"We found that stiffer tissue can cause pancreatic cancer cells to become resistant to chemotherapy, while softer tissue made the cancer cells more responsive to chemotherapy," said Sarah Heilshorn, a professor of materials science and engineering at Stanford and senior author on the paper.

"These results suggest an exciting new direction for future drug development to help overcome chemoresistance, which is a major clinical challenge in pancreatic cancer."

The power of the matrix

The researchers focused their efforts on pancreatic ductal adenocarcinoma, a cancer that starts in the cells lining the ducts of the pancreas and accounts for 90% of pancreatic cancer cases. In these cancers, the network of materials between the cells, known as the extracellular matrix, becomes notably stiffer.

Scientists have theorized that this stiff material acts as a physical block, stopping chemotherapy drugs from reaching cancerous cells, but treatments based on this idea have not been effective in humans.

Heilshorn worked with Ph.D. student Bauer LeSavage, lead author on the paper, to develop a new system to study these changes to the extracellular matrix and better understand their impact on pancreatic cancer cells. They designed three-dimensional materials that mimicked the biochemical and mechanical properties of both pancreatic tumors and healthy pancreas tissues, and used them to culture cells from pancreatic cancer patients, which they received from Calvin Kuo, the Maureen Lyles D'Ambrogio Professor at Stanford Medicine.

"We created a designer matrix that would allow us to test the idea that these cancerous cells might be responding to the chemical signals and mechanical properties in the matrix around them," Heilshorn said.

Using their new system, the researchers selectively activated certain types of receptors in the cancerous cells and adjusted the chemical and physical properties of their designer matrix. They found that pancreatic cancer needed two things to become resistant to chemotherapy: a physically stiff extracellular matrix and high amounts of hyaluronic acid—a polymer that helps stiffen the extracellular matrix and interacts with cells through a receptor called CD44.

Initially, the pancreatic cancer cells in a stiff matrix full of hyaluronic acid responded to chemotherapy. But after some time in these conditions, the cancerous cells became resistant to chemotherapy—they made proteins in the cell membrane that could quickly pump out chemotherapy drugs before they could take effect. The researchers found that they could reverse this development by moving the cells to a softer matrix (even if it was still high in hyaluronic acid) or blocking the CD44 receptor (even if the matrix was still stiff).

"We can revert the cells back to a state where they are sensitive to chemotherapy," Heilshorn said. "This suggests that if we can disrupt the stiffness signaling that's happening through the CD44 receptor, we could make patients' pancreatic cancer treatable by normal chemotherapy."

Steps toward treatments

The discovery that pancreatic cancer cells interact with the stiff matrix around them through CD44 receptors was a surprise, Heilshorn said. Other cancers can be affected by mechanical properties of the extracellular matrix, but these interactions typically work through a different class of receptors called integrins.

"We showed that pancreatic cancer cells weren't really using integrin receptors at all in our materials," Heilshorn said. "That's important, because if you want to design a drug to resensitize patient cells to chemotherapy, you need to know which biological pathway to interfere with."

Heilshorn and her colleagues are continuing to investigate the CD44 receptor and the chain of events that follows after it is activated in a cancerous cell. The more they can reveal about the biological mechanisms that lead to chemoresistance, the easier it will be for drug developers to find a way to disrupt the process.

The researchers are also working to improve their cell culture model, adding new types of cells to better mimic the environment around a tumor, and tweaking it to investigate other mechanical properties beyond stiffness. In addition to opening up new avenues for treating chemoresistance in pancreatic cancer, the researchers hope this work highlights the potential role of the extracellular matrix in cancer progression and the importance of using realistic models to find treatments.

"When we design chemotherapies, we should be testing our cultures in matrices that are relevant to a patient," Heilshorn said. "Because it matters—the way cells respond to drugs depends on the matrix that's around them."

More information: Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids, Nature Materials (2024). DOI: 10.1038/s41563-024-01908-x

https://medicalxpress.com/news/2024-07-reversing-chemotherapy-resistance-pancreatic-cancer.html

'First study to measure toxic metals in tampons shows arsenic and lead, other contaminants'

 Tampons from several brands that potentially millions of people use each month can contain toxic metals like lead, arsenic, and cadmium, a new study led by a UC Berkeley researcher has found. The work is published in the journal Environment International.

Tampons are of particular concern as a potential source of exposure to chemicals, including metals, because the skin of the vagina has a higher potential for chemical absorption than skin elsewhere on the body. In addition, the products are used by a large percentage of the population on a monthly basis—50–80% of those who menstruate use tampons—for several hours at a time.

"Despite this large potential for public health concern, very little research has been done to measure chemicals in tampons," said lead author Jenni A. Shearston, a postdoctoral scholar at the UC Berkeley School of Public Health and UC Berkeley's Department of Environmental Science, Policy, & Management.

"To our knowledge, this is the first paper to measure metals in tampons. Concerningly, we found concentrations of all metals we tested for, including toxic metals like arsenic and lead."

Metals have been found to increase the risk of dementia, infertility, diabetes, and cancer. They can damage the liver, kidneys, and brain, as well as the cardiovascular, nervous, and endocrine systems. In addition, metals can harm maternal health and fetal development.

"Although toxic metals are ubiquitous and we are exposed to low levels at any given time, our study clearly shows that metals are also present in menstrual products, and that women might be at higher risk for exposure using these products," said study co-author Kathrin Schilling, assistant professor at Columbia University Mailman School of Public Health.

Researchers evaluated levels of 16 metals (arsenic, barium, calcium, cadmium, cobalt, chromium, copper, iron, manganese, mercury, nickel, lead, selenium, strontium, vanadium, and zinc) in 30 tampons from 14 different brands.

The metal concentrations varied by where the tampons were purchased (US vs. EU/UK), organic vs. non-organic, and store- vs. name-brand. However, they found that metals were present in all types of tampons; no category had consistently lower concentrations of all or most metals. Lead concentrations were higher in non-organic tampons but arsenic was higher in organic tampons.

Metals could make their way into tampons a number of ways: The cotton material could have absorbed the metals from water, air, soil, through a nearby contaminant (for example, if a cotton field was near a lead smelter), or some might be added intentionally during manufacturing as part of a pigment, whitener, antibacterial agent, or some other process in the factory producing the products.

"I really hope that manufacturers are required to test their products for metals, especially for toxic metals," said Shearston. "It would be exciting to see the public call for this, or to ask for better labeling on tampons and other menstrual products."

For the moment, it's unclear if the metals detected by this study are contributing to any negative health effects. Future research will test how much of these metals can leach out of the tampons and be absorbed by the body, as well as measuring the presence of other chemicals in tampons.

More information: Jenni A. Shearston et al, Tampons as a source of exposure to metal(loid)s, Environment International (2024). DOI: 10.1016/j.envint.2024.108849

https://medicalxpress.com/news/2024-07-toxic-metals-tampons-arsenic-contaminants.html

'First responder' cells in pancreas crucial for blood sugar control

 How does our body control blood sugar so precisely? An international team led by Prof. Nikolay Ninov at the Center for Regenerative Therapies Dresden (CRTD), part of Dresden University of Technology, brought us a step closer to the answer. They found a special group of "first responder" cells in the pancreas that are crucial for triggering blood sugar response.

Their findings were published in the journal Science Advances.

Our bodies need to keep blood sugar levels just right. Too high or too low can be dangerous. This balance is disturbed in diabetes, leading to serious health issues. Beta cells in the pancreas manage this balance by releasing insulin when blood sugar levels rise.

Understanding how beta cells work and coordinate the response to rising blood sugar can ultimately help develop better treatments for diabetes.

Not all beta cells are equal

"Looking at the pancreas, we wondered if all beta cells are actually equally sensitive to sugar. Previous studies suggested some might be more sensitive than others," says Prof. Nikolay Ninov, research group leader at the CRTD in Dresden.

To understand the work of the pancreas, the Ninov team turned to zebrafish. This small tropical fish has a pancreas that works similarly to a human one. At the same time, it offers a huge advantage. Researchers can use transparent fish that have no pigment whatsoever and observe the pancreas at work in real-time in the living fish.

The group discovered that a small group of beta cells are more sensitive to sugar levels than the others. These cells respond to glucose quicker than the rest of the cells, so the Ninov team referred to them as "first responder" cells. They initiate the glucose response, which is followed by the remaining "follower cells."

Hidden hierarchy in the pancreas

The team wanted to test if first responders are necessary for the follower cells to respond to glucose.

Using transparent fish, the Ninov group took advantage of optogenetics, a modern light-based technology that allows to turn single cells on or off with a beam of light.

Turning off the first responder cells lowered the response to the blood sugar of the follower cells. At the same time, when the first responders were selectively activated, the response of the follower cells was enhanced.

"The first responders lie at the top of the beta cell hierarchy when it comes to control of the sugar response. Interestingly, only about 10% of the beta-cells act as first responders. It suggests that this small population of cells serves as a control center for regulating the activity of the rest of the beta cells," explains Prof. Ninov.

Unique traits of first responder cells

To find out what makes the first responder cells unique, the researchers compared the gene expression of highly glucose-sensitive beta cells to those that are less sensitive. They found that first responders are involved in vitamin B6 production. The first responder cells express a key enzyme involved in transforming the inactive form of dietary vitamin B6 into the form that is active in the cells.

In close collaboration with Prof. Guy Rutter's team at the University of Montreal, the researchers turned off the vitamin B6 production in both zebrafish and mouse pancreas. The ability of the beta cells to respond to high blood sugar was dramatically reduced in both species.

"This indicates that vitamin B6 plays an evolutionarily conserved role in the response to glucose. It is possible that the first responders produce and supply Vitamin B6 to the rest of the beta cells to regulate their activity. Checking whether this indeed is the case is one of our next steps," says Prof. Ninov.

Implications for diabetes research

"We now know there are specific cells that start the glucose response and that Vitamin B6 is essential for this process," says Prof. Ninov. Vitamin B6 serves as a cofactor for more than a hundred essential enzymes that play critical roles in the cells, ranging from the control of cellular respiration to neurotransmitter production.

"There is actually a body of research that shows a correlation between low levels of vitamin B6 and incidence of metabolic disease and type 2 diabetes. We would like to focus more on exploring the link there," concludes Prof. Ninov.

Understanding how Vitamin B6 regulates the beta cells in the pancreas could lead to new insights into the pathology of diabetes and ultimately to new treatments.

More information: Luis Fernando Delgadillo-Silva et al, Optogenetic β cell interrogation in vivo reveals a functional hierarchy directing the Ca 2+ response to glucose supported by vitamin B6, Science Advances (2024). DOI: 10.1126/sciadv.ado4513

https://medicalxpress.com/news/2024-07-cells-pancreas-crucial-blood-sugar.html

Key mechanisms identified for regeneration of neurons

 Neurological disorders, such as trauma, stroke, epilepsy, and various neurodegenerative diseases, often lead to the permanent loss of neurons, causing significant impairments in brain function. Current treatment options are limited, primarily due to the challenge of replacing lost neurons.

Direct neuronal reprogramming, a complex procedure that involves changing the function of one type of cell into another, offers a promising strategy.

In cell culture and in living organisms, glial cells—the non-neuronal cells in the central nervous system—have been successfully transformed into functional neurons. However, the processes involved in this reprogramming are complex and require further understanding. This complexity presents a challenge, but also a motivation, for researchers in the field of neuroscience and regenerative medicine.

Modifications in the epigenome

Two teams, one led by Magdalena Götz, Chair of Physiological Genomics at LMU, Head of the Stem Cell Center Department at Helmholtz Munich, and researcher in the SyNergy Cluster of Excellence, and the other led by Boyan Bonev at the Helmholtz Pioneer Campus, explored the molecular mechanisms at play when glial cells are converted to neurons by a single transcription factor.

The findings are published in the journal Nature Neuroscience.

Specifically, the researchers focused on small chemical modifications in the epigenome. The epigenome helps control which genes are active in different cells at different times. For the first time, the teams have now shown how coordinated the epigenome rewiring is, elicited by a single transcription factor.

Using novel methods in epigenome profiling, the researchers identified that a posttranslational modification of the reprogramming neurogenic transcription factor Neurogenin2 profoundly impacts the epigenetic rewiring and neuronal reprogramming. However, the transcription factor alone is not enough to reprogram the glial cells.

In an important discovery, the researchers identified a novel protein, the transcriptional regulator YingYang1, as a key player in this process. YingYang1 is necessary to open up the chromatin for reprogramming, to which end it interacts with the transcription factor.

"The protein YingYang1 is crucial for achieving the conversion from astrocytes to neurons," explains Götz. "These findings are important to understand and improve reprogramming of glial cells to neurons, and thus bring us closer to therapeutic solutions."

More information: Allwyn Pereira et al, Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1, Nature Neuroscience (2024). DOI: 10.1038/s41593-024-01677-5

https://medicalxpress.com/news/2024-07-key-mechanisms-regeneration-neurons.html

Epilepsy drug could keep chemotherapy for stomach cancer working for longer

 Cancer's resistance to chemotherapy could be reversed by targeting lactate—the product that builds up as cancer cells convert nutrients to energy, according to new research published in Nature.

A drug that is currently used to treat epilepsy targets lactate production and, in a pre-clinical study, it re-sensitized stomach cancers to chemotherapy—shrinking tumors and prolonging survival.

Clinical trials have now been initiated to test if the epilepsy drug, called stiripentol, makes chemotherapy work again in people with stomach cancer who have become resistant to treatment.

The early-stage research, led by The Institute of Cancer Research (ICR), London, and Sun Yat-sen University, China, reveals the role that lactate plays in repairing cancer cells' DNA after chemotherapy has damaged it.

Tackling chemotherapy resistance

Chemotherapy attacks cancer by damaging cells' DNA, so cells try to rapidly repair it as they attempt to survive and continue growing.

The researchers examined tissue from 24 patients with stomach cancer, where 15 of the cancers were resistant to chemotherapy and the tumors had continued to grow.

They found that lactate—which builds up in cancer cells as they convert their food source, glucose, to energy in a process called glycolysis that doesn't require oxygen—was most abundant in the chemotherapy-resistant cancer tissues. During glycolysis when there is limited oxygen, glucose is first turned into pyruvate and then lactate, by an enzyme called LDHA.

Targeting lactate build-up

To test if preventing a build-up of lactate could keep chemotherapy working for longer, the researchers targeted the LDHA enzyme with stiripentol. Stiripentol is currently used to treat epilepsy and stops the LDHA enzyme from working.

In mice with stomach cancer, giving stiripentol and chemotherapy reduced the size of tumors—a response which continued to last for four weeks after treatment. The tumors of mice treated with chemotherapy alone shrunk for one week, before starting to grow again.

The mice treated with stiripentol and chemotherapy also survived for longer than those with chemotherapy alone; with chemotherapy, no mice survived for longer than 40 days after treatment, while those with the combination of drugs survived for more than 70 days.

The researchers, some of whom work in the Breast Cancer Now Toby Robins Research Center at the ICR, also found that the lactate is responsible for altering the structure of a key protein involved in DNA repair, called NBS1, and affecting its efficiency.

They examined samples from 94 patients with stomach cancer, prior to chemotherapy treatment. They found that higher levels of alteration of NBS1, higher levels of the NBS1 protein, and higher levels of the LDHA enzyme were all associated with poorer prognosis of the patients after chemotherapy.

The researchers believe that lactate may be responsible for stopping chemotherapy treatment working in other cancers, as levels of LDHA are increased in pancreatic, lung and ovarian cancers.

Professor Axel Behrens, Professor of Stem Cell Biology at The Institute of Cancer Research, London, said, "This extremely promising research has uncovered a likely mechanism for how cancer evades chemotherapy. The discovery that cancer cells create energy in a process that causes a build-up of lactate won the Nobel prize in 1931.

"What we have now found, almost 100 years later, is that lactate has a fundamental impact on cancers' ability to survive, as it boosts the DNA repair process after it has been damaged by chemotherapy treatment.

"In our early-stage study we've seen that you can prevent the build-up of lactate and make a tumor that was resistant to chemotherapy become sensitive again—the treatment continues to work.

"The next step is to test this in a clinical trial, and it would be wonderful if we see the same results in people and give people with cancer precious extra time living well. As we already have a drug to target lactate in clinical use, this discovery could reach patients even sooner."

Professor Kristian Helin, CEO of The Institute of Cancer Research, London, said, "Drug resistance remains one of the biggest challenges we face in treating cancer. While chemotherapy is effective for many patients, we need to stay one step ahead to prevent cancer becoming resistant to it.

"It's clear now that some patients will require a combination of therapies to keep their cancer at bay, and this study indicates an interesting new drug target that could keep chemotherapy working for longer.

"I look forward to seeing this research taken into clinical trials, to see if it could improve the outcome for people with stomach cancer, and hopefully other cancers too."

More information: Hengxing Chen et al, NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance, Nature (2024). DOI: 10.1038/s41586-024-07620-9

https://medicalxpress.com/news/2024-07-epilepsy-drug-chemotherapy-stomach-cancer.html

'About 1 in 8 Americans has been diagnosed with chronic insomnia'

 Millions of Americans struggle to fall or stay asleep, a new survey finds.

Some struggle more mightily than others: Roughly 12% of Americans polled said they have been diagnosed with chronic insomnia, the American Academy of Sleep Medicine (AASM) survey revealed.

Who was the most likely to miss out on good sleep? Men (13%) were slightly more likely than women (11%) to have been diagnosed with chronic insomnia. Meanwhile, millennials reported the highest rate of chronic insomnia diagnosis (15%).

How debilitating can insomnia be? Symptoms associated with insomnia include daytime fatigue or sleepiness; feeling dissatisfied with sleep; having trouble concentrating; feeling depressed, anxious or irritable; and having low motivation or low energy.

"Chronic insomnia impacts not just how a person sleeps at night, but also how they feel and function during the daytime," said AASM President Dr. Eric Olson. "Fortunately, there are effective treatment options for those who are living with chronic insomnia, and these treatments can significantly improve both health and quality of life."

Chronic insomnia can impair physical, mental and emotional health, and it can lead to increased risks for depression, anxiety, substance abuse, motor vehicle accidents, Alzheimer's disease and type 2 diabetes, experts say.

The most effective treatment for chronic insomnia is cognitive behavioral therapy, which combines behavioral strategies such as setting a consistent sleep schedule and getting out of bed when you are struggling to sleep, with thinking strategies, such as replacing fears about sleeplessness with more helpful expectations. While six to eight sessions are typical for treating insomnia, some patients improve more quickly.

"Cognitive behavioral therapy offers patients who are experiencing chronic insomnia a highly personalized plan to help identify any underlying problems and provide long-term solutions that promote healthy sleep," said Michael Nadorff, president of the Society of Behavioral Sleep Medicine.

If you have trouble falling asleep or staying asleep, tell your doctor. Your doctor may refer you to a therapist or an AASM-accredited sleep center for help.

The survey of 2,006 adults throughout the United States was conducted online from May 16-24. The margin of error is plus or minus 2 percentage points.

https://medicalxpress.com/news/2024-07-americans-chronic-insomnia.html

Alzheimer's Association publishes final version of its new diagnostic criteria

 An international team of medical researchers associated with the nonprofit Alzheimer's Association has published a paper describing the group's final version of their new diagnostic criteria for the disease. Published in Nature Medicine, the paper includes use of plasma biomarkers in diagnosing symptomatic Alzheimer's patients.

For many years, the decision to diagnose a patient with Alzheimer's disease during its early stages has been based mostly on symptoms rather than physical tests. In more recent years, researchers have found protein-based biomarkers that can be used to diagnose patients more accurately.

In this new paper, the team at the Alzheimer's Association has formally included results from such tests in its suggestions for doctors making diagnostic decisions for patients suspected of having Alzheimer's disease—but not for those who are asymptomatic.

In their paper, the authors note that biological marker measurements are standard for diagnosing most other biological diseases and suggest that research efforts over the past several years have led to the discovery of markers for Alzheimer's that are strong enough for use in diagnosis.

The team has outlined three major categories of diagnostic biomarkers: core markers of neuropathological changes (specific to Alzheimer's disease); non-core markers not specific to Alzheimer's patients but important to inflammation, immune activation or neurodegeration; and markers of common non-Alzheimer's disease co-pathologies.

The team then breaks down the core markers into two sub-categories; Core 1 and Core 2.

They define Core 1 markers as those that tend to present early in disease progression, such as certain proteins in cerebrospinal fluid, amyloid buildup, and phosphorylated tau in plasma. They further establish criteria for such markers, such as a 42/40 ratio for amyloid beta in cerebrospinal fluid.

They define Core 2 biomarkers as those that become abnormal during later stages of progression and that are more closely associated with symptoms. They include tau PET and tau fragments found in plasma or cerebrospinal fluid. They further suggest that a combination of Core 1 and Core 2 biomarkers may be used to not only diagnose Alzheimer's disease but to provide an indication of its severity.

They note that because their new guidelines are intended for use by doctors seeking to diagnose patients with existing symptoms, it is not likely they could be used to prescribe early therapies to slow its progression.

More information: Clifford R. Jack et al, Revised criteria for the diagnosis and staging of Alzheimer's disease, Nature Medicine (2024). DOI: 10.1038/s41591-024-02988-7

https://medicalxpress.com/news/2024-07-alzheimer-association-publishes-version-diagnostic.html