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Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 8:41am

How aging immune system fuels cancer growth

Why is aging the biggest risk factor for cancer? A new study reveals how an aging immune system spurs tumor growth, offering new insights into cancer prevention and treatment, especially for older adults.

Details on the findings are reported in the September 5 Online First Release of Science.

Cancer is a disease that becomes increasingly common as we age, with the risk rising sharply after the age of 60. Many theories have been proposed, including the cumulative effects of environmentally-induced damage and genetic mutations, but there has been little concrete data explaining why aging drives cancer.

In preclinical models,  a research team found that anakinra, a drug typically used for inflammatory conditions such as rheumatoid arthritis, can be repurposed to block harmful signals between early lung cancer lesions and the bone marrow. This is critical, say the investigators, because as the immune system ages, it creates harmful inflammation that can drive cancer development.

As the immune system ages, it triggers harmful inflammation that can drive cancer growth––by promoting the accumulation of pro-tumor macrophages, a type of immune cell that suppresses the immune effector cells that normally kill tumor cells. This weakens the body's ability to fight cancer.

The researchers found that by blocking specific inflammatory pathways, especially those involving molecules called interleukin-1⍺ (IL-1⍺) and IL-1β, this damaging process could be reversed in mouse models, offering a potential new approach to preventing cancer development in humans.

 

As part of the study, the research team used mouse models to investigate how aging affects cancer progression. They injected tumor cells into mice and observed that lung, pancreatic, and colonic cancer grew more rapidly in older mice compared to younger ones. Using bone marrow transplants from either young or old mice, the investigators simulated the effects of the immune system's aging. The team found that an aged immune system accelerates cancer growth, even in young mice. More strikingly, they found that rejuvenating the immune system significantly reduced cancer growth in older mice.

Using high-dimensional analysis of murine and human cancer tissues, the team identified specific cells and immune-related factors that accelerate cancer growth in the elderly. They then successfully blocked these factors, specifically IL-1⍺/β, demonstrating that inhibiting these molecules can reduce cancer growth in aged mice.

This study shows that an aged immune system promotes cancer progression, independent of the age of the cancer cells or the surrounding tissue. We've long suspected that inflammation can suppress anti-tumor immunity, particularly in older individuals and cancer patients. However, this is the first robust evidence proving that chronic inflammation from an aging immune system predisposes to cancer. 

This study reveals that targeting the aging immune system could significantly reduce cancer risk in older adults. It suggests that enhancing the immune response through immunotherapy might be more effective than directly targeting tumors. 

Part1

Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 8:32am

The trial tested different dosage levels of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and was surgically injected under the retina.

For the first part of the study, cohorts of three adults each received one of the three different dosages: Low, mid, and high. Evaluations were held between each level of dosage to ensure that they were safe before upping the dosage for the next cohort.

A second phase of the study involved only administering the high dosage levels to both an adult cohort of three and a pediatric cohort of three, again after safety reviews of the previous cohorts.

Improvements were noticed quickly, often within the first month, after the therapy was applied and lasted for at least 12 months. Observations of participating patients are also ongoing. Three of six high-dosage patients who were tested to navigate a mobility course in varying levels of light achieved the maximum-possible score. Other tests used eye charts or measured the dimmest flashes of light patients perceived in a dark environment.

Of the nine patients who received the maximum dosage, two had a 10,000-fold improvement in vision.
Primarily, the study sought to determine the safety of the gene therapy and its varying dosage levels. Researchers did find some patients had side effects, but the overwhelming majority were related to the surgical procedure itself.
The most common side effect was conjunctival hemorrhage, the breakage of small blood vessels underneath the clear surface of the eye, which healed. Two patients had eye inflammation that was reversed with a course of steroids. No serious side effects were related to the study drug.
Approval of this experimental medicine for clinical use requires another trial, where participants are randomized to a treatment dose and both patients and those investigating the trial not knowing who gets what. Through that, any possible bias in results could be avoided.

Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study, The Lancet (2024). www.thelancet.com/journals/lan … (24)01447-8/fulltext

Part 2

Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 8:30am

100-fold improvement in sight seen after gene therapy trial

The vision of people with a rare inherited condition that causes them to lose much of their sight early in childhood was 100 times better after they received gene therapy to address the genetic mutation causing it. Some patients even experienced a 10,000-fold improvement in their vision after receiving the highest dose of the therapy, according to researchers from the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.

That 10,000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment.

One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.

A total of 15 people participated in the Phase I/II trial, including three pediatric patients. Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. This specific condition, which affects less than 100,000 people worldwide and is abbreviated as LCA1, causes a significant amount of vision loss as early as infancy.

All subjects had severe vision loss with their best measure of vision being equal or worse than 20/80—meaning if a typically-sighted person could see an object clearly at 80 feet, these patients would have to move up to at least 20 feet to see it.

Glasses provide limited benefit to these patients because they correct abnormalities in the optical focusing ability of the eye, and are unable to address medical causes of vision loss, such as genetic retinal diseases like LCA1.

Part 1

Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 8:24am

Following the discovery of this behavioral principle, the neuroscientists successfully identified the brain mechanism mediating it. They focused on the habenula, a tiny cerebral structure located at the heart of the brain, known to participate in emotional and sensory processing, and to regulate neurotransmitters associated with depression, notably serotonin.

To achieve this, they specifically developed imaging tools to track this molecule in mice.
It is very difficult to measure the variation of serotonin in the brain. Thanks to a biosensor developed by some of the team members, the scientists were able to identify the key mechanism.
Recordings made during behavioral experiments revealed that emotional contagion coincided with a lasting change in the functioning of neurons in the habenula, together with an increase in serotonin release in this region.
By artificially altering the dynamics of serotonin levels, the research team was able to demonstrate that its non-increase not only undermines the long-lasting neuronal activity change in the habenula, but also the ability of mice to foster resilience following adversity.

A common denominator between the mechanism of resilience after adversity discovered in this study and that of depression is serotonin. Many antidepressants target serotonin to increase its concentration in the brain. Here, neuroscientists show that a transient, localized increase in the habenula can prevent the onset of apathetic behavior following a traumatic experience.

This  discovery could also pave the way for new therapeutic applications relevant to depression.

Sarah Mondoloni et al, Serotonin release in habenula during emotional contagion promotes resilience, Science (2024). DOI: 10.1126/science.adp3897. www.science.org/doi/10.1126/science.adp3897

Part 2

Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 8:22am

Neuroscientists uncover serotonin's role in resilience

The simple act of observing others cope with a traumatic experience can increase our capacity for resilience and prevent the pathological states that can result from it, notably depression. Neuroscientists  have demonstrated the presence of this "emotional contagion" in mice, and successfully deciphered its mechanism.

The neurotransmitter serotonin, released in a brain structure called the habenula, has been shown to be the key to resilience.

This discovery, published in Science, revisits the role of serotonin and opens up new perspectives, notably for understanding depression and its treatment.

Human beings have the ability to cope with aversive experiences while continuing to live a normal life. This ability is known as resilience. However, some individuals are more vulnerable to traumatic events. They develop a loss of motivation and drive, which are hallmarks of depression.

Promoting resilience in such people at risk could counter their vulnerability and function as a preventive practice against the possible emergence of a pathological state. But there are still too many unknowns for resilience to be used as a preventive practice.

There is a lack of clinical tools or underlying mechanisms to promote this type of conditioning capable of fostering a resilient reaction as in healthy people. To achieve this, we need to understand the brain function behind adversity.

To explore the underlying brain mechanisms, the neuroscientists first designed an experimental model capable of promoting resilience and measuring its consequences on the appearance of pathological traits following trauma.

They started from the recognized fact that simply observing the emotional experiences of others helps us to learn from them. It's a phenomenon known as emotional contagion, and it engages resilience.

To achieve this, an "observer" mouse was placed close to a mouse subjected to small electric shocks to the paws. This simple task protected the majority of the observer mice from developing pathological states of depression when they were subsequently exposed to this unpleasant experience themselves.

This was not the case for mice who had not witnessed the traumatic experiences of their fellow companions. The scientists concluded that the simple act of observing others cope with a traumatic experience increases one's own capacity for resilience and helps guard against possible pathological consequences.

Part 1

Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 7:39am

The data shows that the more of these spiking hybrid glioma cells a patient has, the better the survival outcome. This information is of great value to patients and their doctors.

 Integrated electrophysiological and genomic profiles of single cells reveal spiking tumor cells in human glioma, Cancer Cell (2024). DOI: 10.1016/j.ccell.2024.08.009. www.cell.com/cancer-cell/fullt … 1535-6108(24)00308-8

Part 2

Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 7:39am

Human brain cancers fire electrical impulses: Researchers reveal unexpected hybrid cell spiking the signals

Researchers  have uncovered a new cell type in the human brain.

The study published in Cancer Cell reveals that a third of the cells in glioma, a type of brain tumor, fire electrical impulses. Interestingly, the impulses, also called action potentials, originate from tumor cells that are part neuron and part glia, supporting the groundbreaking idea that neurons are not the only cells that can generate electric signals in the brain.

The scientists also discovered that cells with hybrid neuron-glia characteristics are present in the non-tumor human brain. The findings highlight the importance of further studying the role of these newly identified cells in both glioma and normal brain function.   

Gliomas are the most common tumors of the central nervous system with an estimated 12,000 cases diagnosed each year. These tumors are universally lethal and have devastating effects on neurological and cognitive functions. Previous studies have shown that patient survival outcomes are associated with tumor proliferation and invasiveness, which are influenced by tumor intrinsic and extrinsic factors, including communication between tumor cells and neurons that reside in the brain.

Researchers have previously described that glioma and surrounding healthy neurons connect with each other and that neurons communicate with tumors in ways that drive tumor growth and invasiveness.

Scientists have known for some time now that tumor cells and neurons interact directly.

To study the ability of glioma cells to spike electrical signals and identify the cells that produce the signals, the team used Patch-sequencing, a combination of techniques that integrates whole-cell electrophysiological recordings to measure spiking signals with single-cell RNA-sequencing and analysis of the cellular structure to identify the type of cells.

The electrophysiology experiments were conducted by the researchers. 

This innovative approach has not been used before to study human brain tumor cells.

The researchers were truly surprised to find these tumor cells had a unique combination of morphological and electrophysiological properties. They had never seen anything like this in the mammalian brain before.

Finding that so many glioma cells are electrically active was a surprise because it goes against a strongly held concept in neuroscience that states that, of all the different types of cells in the brain, neurons are the only ones that fire electric impulses.

These findings show that human cells other than neurons can fire electrical impulses. Since there is an estimated 100 million of these OPCs in the adult brain, the electrical contributions of these cells should be further studied.

Moreover, the comprehensive data analyses revealed that the spiking hybrid cells in glioma tumors had properties of both neurons and OPC cells. Interestingly, they found non-tumor cells that are neuron-glia hybrids, suggesting that this hybrid population not only plays a role in glioma growth but also contributes to healthy brain function. The findings also suggest that the proportion of spiking hybrid cells in glioma may have a prognostic value.

Part1

Comment by Dr. Krishna Kumari Challa on September 6, 2024 at 7:27am

Will humans accept robots that can lie? Scientists find it depends on the lie

Honesty is the best policy… most of the time. Social norms help humans understand when we need to tell the truth and when we shouldn't, to spare someone's feelings or avoid harm. But how do these norms apply to robots, which are increasingly working with humans? To understand whether humans can accept robots telling lies, scientists asked almost 500 participants to rate and justify different types of robot deception.

The scientists selected three scenarios reflecting situations where robots already work—medical, cleaning, and retail work—and three different deception behaviors. These were external state deceptions, which lie about the world beyond the robot, hidden state deceptions, where a robot's design hides its capabilities, and superficial state deceptions, where a robot's design overstates its capabilities.

In the external state deception scenario, a robot working as a caretaker for a woman with Alzheimer's lies that her late husband will be home soon. In the hidden state deception scenario, a woman visits a house where a robot housekeeper is cleaning, unaware that the robot is also filming. Finally, in the superficial state deception scenario, a robot working in a shop as part of a study on human–robot relations untruthfully complains of feeling pain while moving furniture, causing a human to ask someone else to take the robot's place. Hmmm!

The scientists recruited 498 participants and asked them to read one of the scenarios and then answer a questionnaire. This asked participants whether they approved of the robot's behavior, how deceptive it was, if it could be justified, and if anyone else was responsible for the deception. These responses were coded by the researchers to identify common themes and analyzed.

The participants disapproved most of the hidden state deception, the housecleaning robot with the undisclosed camera, which they considered the most deceptive. While they considered the external state deception and the superficial state deception to be moderately deceptive, they disapproved more of superficial state deception, where a robot pretended it felt pain. This may have been perceived as manipulative.

Participants approved most of the external state deception, where the robot lied to a patient. They justified the robot's behavior by saying that it protected the patient from unnecessary pain—prioritizing the norm of sparing someone's feelings over honesty.

Andres Rosero et al, Exploratory Analysis of Human Perceptions of Social Robot Deception Behaviors, Frontiers in Robotics and AI (2024). DOI: 10.3389/frobt.2024.1409712. www.frontiersin.org/journals/r … 9/frobt.2024.1409712

Comment by Dr. Krishna Kumari Challa on September 5, 2024 at 10:11am

Researchers Find Signs Of Dementia In How People Speak

Individuals with memory-related mild cognitive impairment talked less and used fewer but more general nouns.

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12588

Comment by Dr. Krishna Kumari Challa on September 5, 2024 at 9:30am

Insulin and metformin combo aids diabetic foot ulcer healing, new study finds

People with chronic diabetic foot ulcers could soon have a new way to treat their wounds for faster healing and fewer hospital stays. Researchers from Michigan State University and South Shore Hospital have uncovered that the combination of two common diabetes drugs—injectable insulin and orally-administered metformin—increases the amount of metformin at the wound site. As metformin can accelerate wound healing, this could be welcome news for the 18.6 million people worldwide who develop a diabetic foot ulcer, or DFU, in their lifetimes.

Until now, pharmacological studies had not found an interaction between insulin and metformin. This new study shows that there could be at least an indirect role of consuming both insulin and metformin in a way that metformin can end up in a wound area where it enhances the body's capacity to heal.

 Lisa Gould et al, Analysis of Biogenic Amines and Small Molecule Metabolites in Human Diabetic Wound Ulcer Exudate, ACS Pharmacology & Translational Science (2024). DOI: 10.1021/acsptsci.4c00418

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