Tag: Arts

Eradicating Deadly Brain Tumors by ‘Starvation’

A groundbreaking study at Tel Aviv University effectively eradicated glioblastoma, a highly lethal type of brain cancer. The researchers achieved the dramatic outcome using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other supplies the energy required for rapid tumor growth. The researchers found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated.

The study was led by Ph.D. student Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH) in the USA. The paper was published in the scientific journal Brain and was highlighted with special commentary.

Focusing on Tumor Environment

The researchers explain: “Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors.”

“We tackled the challenge of glioblastoma from a new angle,” explains Dr. Mayo. “Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells.”

 

“In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse – indicating that the astrocytes are essential to tumor progression and survival.”

“Specifically, we studied astrocytes – a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their starlike shape. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases. Under the microscope we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumor growth.”

Using a lab model, in which they could eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all lab models with glioblastoma tumors within 4-5 weeks. Applying a unique method to specifically eradicate the astrocytes near the tumor, they observed a dramatic outcome: the cancer disappeared within days, and all treated lab models survived. Moreover, even after discontinuing treatment, most of the lab models survived.

WATCH: Dr. Lior Mayo explains the dramatic breakthrough in addressing glioblastoma, a deadly brain cancer

 

Exposing Mechanisms of Double Agents

“In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse – indicating that the astrocytes are essential to tumor progression and survival,” notes Dr. Mayo. “Therefore, we investigated the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?”

To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors. They found two main differences – thereby identifying the changes that astrocytes undergo when exposed to glioblastoma:

  1. The first change was in the immune response to glioblastoma. Dr. Mayo clarifies, “The tumor mass includes up to 40% immune cells – mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes ‘persuade’ them to ‘change sides’ and support the tumor instead of attacking it. Specifically, we found that the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly – thereby protecting the tumor and facilitating its growth.”
  2. The second change through which astrocytes support glioblastoma is by modulating their access to energy – via the production and transfer of cholesterol to the tumor cells. The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources in the blood barred by the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself – namely in the astrocytes’ ‘cholesterol factory’, which usually supplies energy to neurons and other brain cells. “We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells,” explains Dr. Mayo. “Therefore, we hypothesized that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor.”

The Tumor’s Vulnerability, a Therapeutic Opportunity

Next, the researchers engineered the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumor essentially ‘starved’ to death in just a few days. These remarkable results were obtained in both lab models and glioblastoma samples taken from human patients and are consistent with the researchers’ starvation hypothesis.

 

“The challenge now, is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study.”

 

Dr. Mayo notes: “This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability – the tumor’s dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity.”

The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above. The researchers explain: “For each patient, we examined the expression levels of genes that either neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients.”

“Currently, tools to eliminate the astrocytes surrounding the tumor are available in lab models, but not in humans,” notes Dr. Mayo. “The challenge now, is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors,” he concludes.

Can Music Help Prevent Severe Cognitive Decline?

TAU researchers developed musical tests to detect mental deterioration in old age.

Modern technology contributes to increased longevity and thus to the growth of the elderly population. It is therefore important to take steps to ensure their quality of life, including inventing tools for accessible and quick diagnosis of age-related conditions. While preventative tests are commonly accepted for a variety of physiological problems such as diabetes, high blood pressure or breast cancer, no method has yet been developed to enable routine, accessible monitoring of the brain for cognitive issues.

 

Researchers at Tel Aviv University have developed a method that employs musical tests and a portable instrument for measuring brain activity to detect cognitive decline in old age. The method entails measuring 15 minutes of electrical activity in the subject’s brain while he or she performs simple musical tasks and can be easily implemented by any staff member in any clinic, without requiring special training. The researchers believe the method could pave the way towards early detection of cognitive decline when treatment and prevention of severe decline are possible, improving the quality of life of millions around the world

 

Many Powers of Music

The study was led at Tel Aviv University by PhD student Neta Maimon from the School of Psychological Sciences and the Buchmann-Mehta School of Music, and Lior Molcho from Neurosteer Ltd, headed by Prof. Nathan Intrator from the Blavatnik School of Computer Science and the Sagol School of Neuroscience. Other participants included: Adi Sasson, Sarit Rabinowitz, and Noa Regev-Plotnick from the Dorot-Netanya Geriatric Medical Center. The article was published in the journal Frontiers in Aging Neuroscience.

 

As part of the study, the researchers developed a groundbreaking method combining a portable device for the measurement and innovative analysis of electroencephalography (EEG), developed by Neurosteer, and a short musical test of about 12-15 minutes, developed by Maimon.

 

“We have actually succeeded in illustrating that music is indeed an effective tool for measuring brain activity.”

 

Maimon, who specializes in musical cognition, explains that music has great influence on different centers in the brain. On the one hand, music is known to be a quick mood stimulant, particularly of positive emotion. On the other hand, in different situations, music can be cognitively challenging, activating the frontal parts of the brain, especially if we try to concentrate on different aspects of the music, and at the same time perform a particular task. According to Maimon, if we combine these two capabilities, we can create cognitive tests that are quite complex, yet also pleasant and easy to perform.

 

Neta Maimon specializes in musical cognition

 

Furthermore, music that is positive and reasonably rhythmic will enhance concentration and performance of the task. Thus, for example, the famous “Mozart effect,” whereby subjects perform better on intelligence tests after listening to Mozart’s music, has nothing to do with Mozart’s music, but rather the fact that music creates a positive mood and stimulates us to a state that is optimal for performing intelligence and creativity tests.

 

Accordingly, the researchers hypothesized that with musical tools, it would also be possible to challenge the subjects to an extent that would enable testing of the brain’s frontal activity as well as raising their spirits, thus enhancing their performance on the test while the overall experience is pleasant.

 

Enabling Early Detection of Cognitive Decline

The study included an experiment testing 50 elderly people hospitalized at the Dorot-Netanya Geriatric Medical Center. “Anyone hospitalized at Dorot, or any other geriatric rehabilitation institution, undergoes a standard test called ‘mini-mental,’ designed to evaluate their cognitive condition as a routine part of the intake process,” explains Maimon.

 

During the test, the subject is connected to the portable EEG device by means of an adhesive band with three electrodes attached to the forehead. The test includes a variety of tasks, including enumerating the days of the week or months of the year backwards. The subject performs a series of musical-cognitive tasks according to audible instructions given automatically through earphones. Short melodies are played by different instruments, and the subjects are instructed to perform various tasks on them at varying levels of difficulty. For example, pressing a button each time any melody is played or pressing it only when the violin plays. In addition, the test includes several minutes of musically guided meditation designed to bring the brain to a resting state, as this state is known to indicate cerebral functioning in various situations. Up to 30 points can be accrued, a high score indicating normal cognition.

 

“Our method enables the monitoring of cognitive capability and detection of cognitive decline already in the early stages, all by simple and accessible means.”

 

“The participants scored 18-30 on the mini-mental test, indicating various levels of cognitive functioning,” explains Maimon. “The EEG device registered the electrical activity in the brain during the activity, and the results were analyzed using machine learning technology. This allowed mathematical indices to be identified that were precisely correlated with the mini-mental test scores; in other words, we obtained new neuro-markers [brain markers] that may stand alone as indices of the subject’s cognitive status.”

 

Maimon adds: “We have actually succeeded in illustrating that music is indeed an effective tool for measuring brain activity. The brain activity and response times to tasks correlated to the subjects’ cerebral conditions (correlating to the mini-mental score assigned to them). More importantly, all those who underwent the experiment reported that, on the one hand, it challenged the brain, but on the other it was very pleasant to perform”.

 

The researchers conclude: “Our method enables the monitoring of cognitive capability and detection of cognitive decline already in the early stages, all by simple and accessible means, with a quick and easy test that can be conducted in any clinic. This method is of special importance today due to the increase in longevity and accelerated population growth, particularly among the elderly. Today, millions of people around the world already suffer or are liable to suffer soon from cognitive decline and its dire consequences, and their number will only increase in the coming decades. Our method could pave the way towards efficient cognitive monitoring of the general population, and thus detect cognitive decline in its early stages, when treatment and prevention of severe decline are possible. It is therefore expected to improve the quality of life of millions around the world.”

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