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Tag: Medicine

Slowing Down Skin Cancer

Tel Aviv University researchers decipher the mechanism that enables skin cancer to metastasize to the brain – delaying its spread by 80%.

Once melanoma, or skin cancer, spreads to the brain, it becomes extremely aggressive. Individuals with this stage of cancer are given an average 15 months to live, and that is following surgery, radiation, and chemotherapy. Researchers from Tel Aviv University deciphered, for the first time, a mechanism that enables skin cancer to metastasize to the brain and managed to delay the spread of the disease by 60% to 80% (depending on the stage of the intervention) using existing treatments.

 

The encouraging study was led by Prof. Ronit Satchi-Fainaro and Ph.D. student Sabina Pozzi of the Sackler Faculty of Medicine at Tel Aviv University. The results were published in the scientific journal JCI Insight.

 

“In an advanced stage, 90% of melanoma patients will develop brain metastases. This is a puzzling statistic. We expect to see metastases in the lungs and liver, but the brain is supposed to be a protected organ.”

 

How do the Cancer Cells Infiltrate the Brain?

“In an advanced stage, 90% of melanoma [/skin cancer] patients will develop brain metastases,” explains Prof. Satchi-Fainaro. “This is a puzzling statistic. We expect to see metastases in the lungs and liver, but the brain is supposed to be a protected organ. The blood-brain barrier keeps harmful substances from entering the brain, and here it supposedly doesn’t do the job—cancer cells from the skin circulate in the blood and manage to reach the brain. We asked ourselves with ‘whom’ the cancer cells ‘talk’ to in the brain to infiltrate it.”

 

The researchers found that in melanoma patients with brain metastases, the cancer cells “recruit” cells called ‘astrocytes’, star-shaped cells found in the spinal cord and brain which are responsible for maintaining stable conditions (/homeostasis) in the brain.

 

“The astrocytes are the first to come to correct the situation in the event of a stroke or trauma, for example,” says Prof. Satchi-Fainaro, “and it is with them that the cancer cells interact, exchanging molecules and corrupting them.”

 

Protecting the Brain’s Border Guards

“Moreover, the cancer cells recruit the astrocytes so that they do not inhibit the spread of the metastases. As such, they create local inflammation in the melanoma cells-astrocytes interaction areas that increase the permeability through the blood-brain barrier, as well as the division and migration of the cancer cells.”

 

“The communication between them is reflected in the fact that the astrocytes begin to secrete a protein that promotes inflammation called MCP-1 (also known as CCL2), and in response to this, the cancer cells begin to express its receptors CCR2 and CCR4, which we suspected to be responsible for the destructive communication with the astrocytes.”

 

“Both the antibody and the small molecule we used (…) have already been tested on humans as part of clinical trials. Therefore, these treatments are considered safe, and we can try to repurpose them for melanoma.”

 

To test their hypothesis, Prof. Satchi-Fainaro and her team tried to inhibit the expression of the protein and its receptors in genetically engineered lab models and in 3D models of primary melanoma and brain metastases. To this end, the researchers used both an antibody (biological molecule) and a small molecule (synthetic), designed to block the MCP-1 protein. They also employed CRISPR technology, a gene-editing technique, to genetically edit the cancer cells and cut out the two genes that express the two relevant receptors, CCR2 and CCR4. With each of the methods, the researchers were able to delay the spread of metastases.

 

“These treatments succeeded in delaying the penetration of the cancer cells into the brain and their subsequent spread throughout the brain,” says Prof. Satchi-Fainaro. The team succeeded in achieving a 60% to 80% delay, depending on the stage of the intervention. They achieved the best results with the treatment conducted immediately after surgery to remove the primary melanoma and were able to prevent the metastases from penetrating the brain.

 

“I believe that the treatment is suitable for the clinic as a preventive measure,” says Satchi-Fainaro. “Both the antibody and the small molecule we used—which are primarily intended to treat sclerosis, diabetes, liver fibrosis, and cardiovascular diseases, as well as serve as a biomarker for other types of cancer—have already been tested on humans as part of clinical trials. Therefore, these treatments are considered safe, and we can try to repurpose them for melanoma.”

 

The research was conducted in collaboration with additional scientists and physicians from Tel Aviv University, including Prof. Adi Barzel, Dr. Asaf Madi, Prof. Iris Barshack, Prof. Eran Perlson, and Prof. Inna Slutsky. International researchers also participated in the study, including Prof. Eytan Ruppin from the US National Institutes of Health (NIH), Prof. Henry Brem and Thomas Hyde from Johns Hopkins University-, and Prof. Helena Florindo from the University of Lisbon.

 

The study was funded by the European Research Council (ERC), the Melanoma Research Alliance (MRA), the Kahn Foundation, the Israel Cancer Research Fund (ICRF), and the Israel Science Foundation (ISF).

 

Featured image: Ph.D. student Sabina Pozzi and Prof. Ronit Satchi-Fainaro

Covid-19 Antibodies May Eliminate Need for Boosters

Breakthrough TAU discovery can neutralize all known Covid variants.

A team of Tel Aviv University researchers has demonstrated that antibodies isolated from the immune system of recovered COVID-19 patients are effective in neutralizing all known strains of the virus, including the Delta and the Omicron variants. The discovery may eliminate the need for repeated booster vaccinations and strengthen the immune system of populations at risk.

 

The research was led by Dr. Natalia Freund and doctoral students Michael Mor and Ruofan Lee of the Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine and of the TAU Center for Combating Pandemics. The study was conducted in collaboration with Dr. Ben Croker of the University of California San Diego. Prof. Ye Xiang of Tsinghua University in Beijing. Prof. Meital Gal-Tanamy and Dr. Moshe Dessau of Bar-Ilan University also took part in the study. The study was published in the Nature journal Communications Biology.

 

Highly Effective Against Delta and Omicron

The present study is a continuation of a preliminary study conducted in October 2020, at the height of the COVID-19 crisis. At that time, Dr. Freund and her colleagues sequenced all the B immune system cells from the blood of people who had recovered from the original COVID strain in Israel, and isolated nine antibodies that the patients produced. The researchers now found that some of these antibodies are very effective in neutralizing the new coronavirus variants, Delta and Omicron.

 

“In the previous study, we showed that the various antibodies that are formed in response to infection with the original virus are directed against different sites of the virus,” says Dr. Freund. “The most effective antibodies were those that bound to the virus’s ‘spike’ protein, in the same place where the spike binds the cellular receptor ACE2. Of course, we were not the only ones to isolate these antibodies, and the global health system made extensive use of them until the arrival of the different variants of the coronavirus, which in fact rendered most of those antibodies useless.”

 

“In the current study, we proved that two other antibodies, TAU-1109 and TAU-2310, which bind the viral spike protein in a different area from the region where most of the antibodies were concentrated until now (and were therefore less effective in neutralizing the original strain) are actually very effective in neutralizing the Delta and Omicron variants. According to our findings, the effectiveness of the first antibody, TAU-1109, in neutralizing the Omicron strain is 92%, and in neutralizing the Delta strain, 90%. The second antibody, TAU-2310, neutralizes the Omicron variant with an efficacy of 84%, and the Delta variant with an efficacy of 97%.”

 

Can Serve as Effective Substitute for Boosters

According to Dr. Freund, the surprising effectiveness of these antibodies might be related to the evolution of the virus: “The infectivity of the virus increased with each variant because each time, it changed the amino acid sequence of the part of the spike protein that binds to the ACE2 receptor, thereby increasing its infectivity and at the same time evading the natural antibodies that were created following vaccinations.”

 

“In contrast, the antibodies TAU-1109 and TAU-2310 don’t bind to the ACE2 receptor binding site, but to another region of the spike protein – an area of ​​the viral spike that for some reason does not undergo many mutations – and they are therefore effective in neutralizing more viral variants. These findings emerged as we tested all the known COVID strains to date.”

 

“In our view, targeted treatment with antibodies and their delivery to the body in high concentrations can serve as an effective substitute for repeated boosters, especially for at-risk populations and those with weakened immune systems.” 

 

The two antibodies, cloned in Dr. Freund’s laboratory at Tel Aviv University, were sent for tests to check their effectiveness against live viruses in laboratory cultures at the University of California San Diego, and against pseudo viruses in the laboratories of the Faculty of Medicine of Bar-Ilan University in the Galilee; the results were identical and equally encouraging in both tests.

 

Dr. Freund believes that the antibodies can bring about a real revolution in the fight against COVID-19: “We need to look at the COVID-19 pandemic in the context of previous disease outbreaks that humankind has witnessed. People who were vaccinated against smallpox at birth and who today are 50 years old still have antibodies, so they are probably protected, at least partially, from the monkeypox virus that we have recently been hearing about. Unfortunately, this is not the case with the coronavirus. For reasons we still don’t yet fully understand, the level of antibodies against COVID-19 declines significantly after three months, which is why we see people getting infected again and again, even after being vaccinated three times.”

 

“In our view, targeted treatment with antibodies and their delivery to the body in high concentrations can serve as an effective substitute for repeated boosters, especially for at-risk populations and those with weakened immune systems. COVID-19 infection can cause serious illness, and we know that providing antibodies in the first days following infection can stop the spread of the virus. It is therefore possible that by using effective antibody treatment, we will not have to provide booster doses to the entire population every time there is a new variant.”

Featured image: Dr. Natalia Freund from the Sackler Faculty of Medicine (Photo: Yoram Reshef)

Scientific discovery may facilitate speedy, objective, and accurate diagnosis of the condition using saliva

Scientific discovery may facilitate speedy, objective, and accurate diagnosis of the condition using saliva.

A scientific breakthrough from the Tel Aviv and Haifa Universities may facilitate speedy, objective, and accurate diagnosis of people suffering from posttraumatic stress disorder, PTSD, using saliva samples, as well as developing microbiotic related medications (associated with the body’s microbial ecology).

 

The study was a joint effort by eminent scholars from various fields. It was led by Professor Illana Gozes and included Professor Noam Shomron, Dr. Shlomo Sragovich and Ph.D. student Guy Shapira, (all from TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience) as well as Prof. Zahava Solomon from TAU’s Gershon H. Gordon Faculty of Social Sciences, and Prof. Abraham Sagi-Schwartz and PhD student Ella Levert-Levitt from the Center for the Study of Child Development and the School of Psychological Sciences at Haifa University. The study was published in NATURE‘s prestigious MOLECULAR PSYCHIATRY magazine.

 

Diagnosing PTSD by Objective Criteria

The researchers tested a unique group of about 200 Israeli veteran soldiers (they all came from a larger cohort of subjects from a comprehensive four-decade-long study of veterans by Prof. Solomon) who had fought in the first Lebanon War in 1982. The test covered various psychological aspects, including sleep, appetite disorders, guilt, suicidal thoughts, social and spousal support, hostility, satisfaction with life, as well as issues of demographics, psychopathology, welfare, health, and education.

 

“We were surprised to discover that about a third of the PTSD subjects had never been diagnosed with post-trauma, so they never received any recognition from the Ministry of Defense and the official authorities.”

 

The researcher also collected saliva samples from them and comparing the results of the subjects’ microbial distribution to the psychological results and their responses to the welfare questionnaires, the researchers from the universities of Tel Aviv and Haifa found that people with PTSD and high psychopathological indications exhibit the same picture of bacteria in the saliva (a unique oral microbiotic signature).

According to the researchers, this study is significant in that for the first time, we might be able to diagnose post-trauma by objective criteria and not just behavioral ones.

One Third of Soldiers Were Undiagnosed

It is interesting to note here that the saliva bacteria of those exposed to air pollution showed a correlation to the picture with PTSD, while the number of years of education showed a protective influence and a reverse picture of the microbial ecology in the saliva. 

 

“To the best of our knowledge, this is the first depiction of a microbial signature in the saliva among veteran soldiers with PTSD,” says Prof. Illana Gozes. “We were surprised to discover that about a third of the PTSD subjects had never been diagnosed with post-trauma, so they never received any recognition from the Ministry of Defense and the official authorities.”

 

“To the best of our knowledge, this is the first depiction of a microbial signature in the saliva among veteran soldiers with PTSD,”

 

“It must be stressed that until now, post-trauma diagnosis has been based solely on psychological and psychiatric measures. Thanks to this study, it may be possible, in the future, to use objective molecular and biological characteristics to distinguish PSTD sufferers, taking into account environmental influences. We hope that this new discovery and the microbial signatures described in this study might promote easier diagnosis of post-traumatic veteran soldiers so they can receive appropriate treatment.”

The study was also supported by IDF’s Medical Corps Department of Health and Well-Being and Dr. Ariel Ben Yehuda, former chief of the above Department and currently, a Department Manager in the Mental Health Medical Center in Shalvata, Clallit Health Services. The study also involved collaboration with the Charité University Medicine in Berlin and its microbiology experts Dr. Markus M. Heimesaat and Professor Stefan Bereswill, as well as with the University of Hong Kong, which is studying the effects of air pollution, Professors Victor Li and Jacqueline Lam.

Tiny Molecule Makes Big Impact on Cancer Treatment

Newly discovered molecule may allow for more accessible and effective cancer immunotherapies.

Researchers at Tel Aviv University and the University of Lisbon have discovered a potentially new immunotherapy, which may lead to more affordable and effective treatments. Immunotherapy activates the patient’s immune system to fight cancer cells.

In this significant step in the fight against cancer, the researchers used computational and bioinformatic systems to discover a tiny molecule which can enter a solid tumor. Thanks to its low molecular weight, the molecule outperforms existing antibodies that are used as the key component in many cancer immunotherapies today. The molecule is also small enough that it may one day be administered in a pill form, saving stressful and time-consuming trips to the hospital.

Behind the groundbreaking development is an international team of researchers led by Prof. Ronit Sachi-Fainaro, Director of the Center for Cancer Biology Research and Head of the Laboratory for Cancer Research and Nanomedicine at the Sackler Faculty of Medicine at Tel Aviv University, along with Prof. Helena Florindo and Prof. Rita Guedes from the Research Institute for Medicines at the Faculty of Pharmacy, University of Lisbon. The results of the study were published in the Journal for ImmunoTherapy of Cancer.

Making Effective Immunotherapy Accessible

Immunotherapies can significantly improve patient recovery rates, without the severe side effects that accompany treatments such as chemotherapy. Immunotherapies often make use of antibodies, which are similar to proteins produced by the immune system to destroy infection-causing organisms. However, while lab-grown antibodies created to fight cancer have demonstrated some success, they are costly and not always effective.

 

“I believe that in the future, the small molecule will be commercially available and will make immunotherapy affordable for cancer patients.”

 

Considering these challenges, TAU and University of Lisbon researchers used computational, bioinformatics and data analysis tools to evaluate thousands of molecular structures. They discovered a list of potential candidates and used the best structure they found to synthesize the new, small molecule which has successfully activated immune cells against cancer cells in lab models, including patient-derived ones. 

The creation of this small molecule builds on the research of Nobel Prize winners James Allison and Tasuku Honjo, who originally developed the CTLA-4 and PD-1 antibodies, respectively, which are used in today’s cancer immunotherapies. The two discovered that immune cells are essentially disabled by particular proteins found in cancer and immune cells. The protein called PD-L1 is found in cancer cells, and paralyzes immune cells by binding to a protein on these cells called PD-1. Honjo’s antibodies neutralize the PD-1/PD-L1 protein bond, allowing the immune system to attack the cancer. 

 

“Patients will probably be able to take it at home, orally, without the need for IV administration in the hospital.”

 

Prof. Satchi-Fainaro, head of the TAU research team and a 2020 Kadar Family Award winner, explains that whereas lab-grown antibodies have complex structures and are expensive to produce, the new molecule was synthesized with simple equipment at a low cost. “I believe that in the future, the small molecule will be commercially available and will make immunotherapy affordable for cancer patients.” 

The small molecule is also better equipped to penetrate a solid tumor than previous treatments. The antibodies used for current treatments enter a tumor via its blood vessels. “If there are fewer blood vessels in a particular area of ​​the tumor, the antibody will not be able to get inside. The small molecule, on the other hand, diffuses, and is therefore not entirely dependent on the tumor’s blood vessels or on its hyper-permeability,” says Prof. Satchi-Fainaro. “Another advantage of the small molecule is that it may be available in a format that patients will probably be able to take at home, orally, without the need for intravenous injections in the hospital.”

This work was supported by Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) and by The Israeli Ministry of Health under the frame of EuroNanoMed-II, “La Caixa” Foundation, Liga Portuguesa Contra o Cancro, the European Research Council (ERC), The Israel Science Foundation, The Melanoma Research Alliance (MRA), the Israel Cancer Research Fund (ICRF) Professorship award and the Morris Kahn Foundation. 

Featured image: Prof. Ronit Satchi-Fainaro in her lab

New Learning Method for People with Autism

Could accelerate learning process and improve visual perception capabilities.

A new study from Tel Aviv University proposes a new learning method for people with autism that may accelerate the learning process and significantly improve capabilities in terms of visual perception. According to the researchers, improving the perceptual capacity of people with autism is often a challenge, and usually requires long and tedious training alongside additional learning challenges that characterizes autism, such as the ability to generalize learning to new situations.

The study was conducted by doctoral student Shira Klorfeld-Auslender and Prof. Nitzan Censor from the School of Psychological Sciences and the Sagol School of Neuroscience at Tel Aviv University, in collaboration with Prof. Ilan Dinstein and his team from Ben-Gurion University. The study was published in the journal Current Biology.

 

“A large part of learning does not happen in formal training settings but afterwards, through processes of assimilation and reinforcement of memory that occur in an ‘offline’ state; for example, when our brain is asleep.”

 

Longer Not Necessarily Better

The new method proposed by the researchers is based on utilizing “memory flashes,” by exposing a person for just a few seconds to a task that has already been learned. While standard teaching practice reinforce length and repetition of new skills, the new method improved both visual perception capabilities and the generalization of learning through helping the subjects excel in the same tasks, under different conditions.

“In my laboratory, we focus on the study of learning in humans, and we know that a large part of learning does not happen in formal training settings but afterwards, through processes of assimilation and reinforcement of memory that occur in an ‘offline’ state; for example, when our brain is asleep,” explains Prof. Censor.

“However, standard teaching methods still advocate an approach where longer practice equals better learning: if you want to play the piano, you should practice playing the piano for many hours every day until the playing becomes second nature to you. We have identified an alternative learning mechanism that uses ‘memory flashes’ – a brief exposure to a task that has already been learned –to assimilate and generalize skill developed.”

 

Prof. Nitzan Censor

 

Effective with Added Value

In the study, 30 high-functioning adults with autism were asked to learn a visual task (for example, identifying the direction of lines that appear for a few milliseconds on the screen). However, instead of repeating the task for a long time each day, the examinees in the main experimental group learned the task in depth on the first day, and in the following days they were exposed to the visual stimulus for only a few seconds. At the end of the process, although the study participants studied the task for a minimal amount of time, their performance improved significantly, by about 20–25%, which was a similar result to those subjected to multiple-repetition learning and to the achievements of subjects without autism.

 

“We have shown that it does not take prolonged practice time to assimilate the task – it is enough to flash it for a few seconds to stimulate the relevant brain network, and the brain will then assimilate the material on its own.”

 

Moreover, even when presented with the task under new conditions (for example, when the stimulus was learned in a new location), the examinees who learned with the memory flash method performed better than those in the control group – they knew how to generalize the skills learned in the first task. The participants’ success in generalizing the learning to other situations is considered significant, as these are skills that people with autism tend to struggle with.

“We have already proven in previous studies that processes of learning assimilation can be improved through flashes of memory,” says Prof. Censor. “We have shown that it does not take prolonged practice time to assimilate the task – it is enough to flash it for a few seconds to stimulate the relevant brain network, and the brain will then assimilate the material on its own.”

“In this case, we tested people with autism. People with autism often have difficulty learning and generalizing repetitive learning, that is, using tools that have also been learned when executing new tasks. Through short flashes of visual stimulus of a task learned, we were able to produce learning that is identical to repetitive learning in terms of its effectiveness; meaning, we significantly shortened the learning time. The added value is the ability to generalize: the examinees performed a task under new conditions, as if they had fully learned it. “

According to Prof. Censor, the new method may have significant potential implications in a wide range of areas. The new study could pave the way for more meaningful approaches to learning for people with autism, and in a wide variety of tasks. Moreover, the method may contribute to shorten rehabilitation after neurological injuries.

CRISPR Therapeutics can Damage the Genome

TAU Researchers caution that while the genome editing method is very effective, it is not always safe and can promote cancer.

A new study from TAU identifies risks in the use of CRISPR therapeutics – an innovative, Nobel-prize-winning method that involves cleaving and editing DNA, already employed for the treatment of conditions like cancer, liver and intestinal diseases, and genetic syndromes.

Investigating the impact of this technology on T-cells (white blood cells of the immune system), the researchers detected a loss of genetic material in a significant percentage – up to 10% of the treated cells. They explain that such loss can lead to destabilization of the genome, which might cause cancer.

The study was led by Dr. Adi Barzel from the School of Neurobiology, Biochemistry and Biophysics at TAU’s George S. Wise Faculty of Life Sciences and Dotan Center for Advanced Therapies, a collaboration between the Tel Aviv Sourasky Medical Center (Ichilov) and Tel Aviv University, and by Dr. Asaf Madi and Dr. Uri Ben-David from TAU’s Sackler Faculty of Medicine and Edmond J. Safra Center for Bioinformatics. The findings were published in the leading scientific journal Nature Biotechnology.

Cleavage Risk

The researchers explain that CRISPR is a groundbreaking technology for editing DNA – cleaving DNA sequences at certain locations to delete unwanted segments, or alternately repair or insert beneficial segments. Developed about a decade ago, the technology has already proved impressively effective in treating a range of diseases – cancer, liver diseases, genetic syndromes, and more.

The first approved clinical trial ever to use CRISPR, was conducted in 2020 at the University of Pennsylvania, when researchers applied the method to T-cells – white blood cells of the immune system. Taking T-cells from a donor, they expressed an engineered receptor targeting cancer cells, while using CRISPR to destroy genes coding for the original receptor – which otherwise might have caused the T-cells to attack cells in the recipient’s body.  

 

“CRISPR therapeutics, in which DNA is cleaved intentionally as a means for treating cancer, might, in extreme scenarios, actually promote malignancies.”

 

In the present study, the researchers sought to examine whether the potential benefits of CRISPR therapeutics might be offset by risks resulting from the cleavage itself, assuming that broken DNA is not always able to recover.

Dr. Ben-David and his research associate Eli Reuveni explain, “The genome in our cells often breaks due to natural causes, but usually it is able to repair itself, with no harm done. Still, sometimes a certain chromosome is unable to bounce back, and large sections, or even the entire chromosome, are lost. Such chromosomal disruptions can destabilize the genome, and we often see this in cancer cells. Thus, CRISPR therapeutics, in which DNA is cleaved intentionally as a means for treating cancer, might, in extreme scenarios, actually promote malignancies.”

To examine the extent of potential damage, the researchers repeated mentioned 2020 Pennsylvania experiment, cleaving the T-cells’ genome in the same locations – chromosomes 2, 7, and 14 (of the human genome’s 23 pairs of chromosomes). Using a state-of-the-art technology called ‘single-cell RNA sequencing’ they analyzed each cell separately and measured the expression levels of each chromosome in every cell.

Significant Loss of Genetic Material

A significant loss of genetic material was detected in some of the cells. For example, when Chromosome 14 had been cleaved, about 5% of the cells showed little or no expression of this chromosome. When all chromosomes were cleaved simultaneously, the damage increased, with 9%, 10%, and 3% of the cells unable to repair the break in chromosomes 14, 7, and 2 respectively. The three chromosomes did differ, however, in the extent of the damage they sustained. 

“Single-cell RNA sequencing and computational analyses enabled us to obtain very precise results,” explain Dr. Madi and his student Ella Goldschmidt, adding: “We found that the cause for the difference in damage was the exact place of the cleaving on each of the three chromosomes. Altogether, our findings indicate that over 9% of the T-cells genetically edited with the CRISPR technique had lost a significant amount of genetic material. Such loss can lead to destabilization of the genome, which might promote cancer.”

 

“We advance this highly effective technology, while at the same time cautioning against its potential dangers. This may seem like a contradiction, but as scientists we are quite proud of our approach, because we believe that this is the very essence of science: we don’t ‘choose sides.'”

 

Researchers Not ‘Choosing Sides’

Based on their findings, the researchers caution that extra care should be taken when using CRISPR therapeutics. They also propose alternative, less risky, methods, for specific medical procedures, and recommend further research into two kinds of potential solutions: reducing the production of damaged cells or identifying damaged cells and removing them before the material is administered to the patient.

Dr. Barzel and his PhD student Alessio Nahmad conclude: “Our intention in this study was to shed light on potential risks in the use of CRISPR therapeutics. We did this even though we are aware of the technology’s substantial advantages. In fact, in other studies we have developed CRISPR-based treatments, including a promising therapy for AIDS. We have even established two companies – one using CRISPR and the other deliberately avoiding this technology. In other words, we advance this highly effective technology, while at the same time cautioning against its potential dangers. This may seem like a contradiction, but as scientists we are quite proud of our approach, because we believe that this is the very essence of science: we don’t ‘choose sides.’ We examine all aspects of an issue, both positive and negative, and look for answers.”

Tel Aviv University Researchers Develop Long Covid Treatment

High-pressure oxygen therapy is now available for millions suffering from long Covid.

A groundbreaking new study from Tel Aviv University, the first of its kind in the world, found a promising treatment for long-term COVID-19 symptoms, based on advanced hyperbaric (high-pressure oxygen) therapy (HBOT).

Long COVID, which affects up to 30% of patients infected by the COVID-19 virus, is characterized by a range of debilitating cognitive symptoms such as inability to concentrate, brain fog, forgetfulness and difficulty recalling words or thoughts – persisting for more than three months, and sometimes up to two years. To date, no effective therapy has been suggested, leaving many millions of sufferers around the world with no remedy.

The researchers: “Our study is the first randomized controlled trial to demonstrate a real solution for long COVID. Patients exposed to an intensive protocol of Hyperbaric Oxygen Therapy treatments showed significant improvement compared to the control group. For millions suffering from long-term COVID-19 symptoms, the study provides new hope for recovery.”

Long Covid – Detrimental to Quality of Life

The study was conducted by the Sagol Center for Hyperbaric Medicine and Research at Tel Aviv University and the Shamir Medical Center (Assaf Harofeh). It was led by Prof. Shai Efrati, Director of the Sagol Center and a faculty member at TAU’s Sackler School of Medicine and Sagol School of Neuroscience, and by Dr. Shani-Itskovich Zilberman from the Sagol Center for Hyperbaric Medicine and TAU’s Sackler School of Medicine. Other chief contributors were Dr. Merav Catalogna, lead data scientist from the Shamir Medical Center (Assaf Harofeh), and Dr. Amir Hadanny from the Sagol Center and TAU’s Sackler School of Medicine. The paper was published in Scientific Reports.

Prof. Efrati explains: “Today, we understand that in some patients, the COVID-19 virus penetrates the brain through the cribriform plate, the part of the skull located just above our nose, and triggers chronic brain injury – mainly in brain regions in the frontal lobe, responsible for cognitive function, mental status and pain interpretation. Consequently, affected patients experience a long-term cognitive decline, with symptoms such as brain fog, loss of concentration and mental fatigue. In addition, since the frontal lobe is damaged, patients may suffer from mood disturbance, depression, and anxiety.”

According to Efrati, these clinical symptoms, identified in patients all over the world, were corroborated by the World Health Organization in an official definition of so-called ‘long COVID’ issued in October 2021, including cognitive dysfunction as one of the common symptoms. A recent study from the Universities of Cambridge and Exeter reported that 78% of long-term COVID-19 patients experienced difficulties with concentration, 69% reported brain fog, and 68% reported forgetfulness. “Thus, long-term COVID-19 effects can be very detrimental to the sufferer’s quality of life,” continues Efrati, “and no effective treatment has yet been found.”

 

Prof. Shai Efrati

 

HBOT – Proven Effective Against other Brain Injuries

“In our study, we harnessed Hyperbaric Oxygen Therapy, already proven effective in the treatment of other forms of brain injury such as stroke, trauma, age-related cognitive decline and treatment-resistant PTSD, to the global effort to find a solution for long COVID-19,” explains Efrati.

 

The study, designed as a prospective, randomized, double-blind, placebo-controlled clinical trial, included 73 patients with reported post-COVID-19 cognitive symptoms such as inability to concentrate, brain fog, forgetfulness and difficulty recalling words or thoughts, persisting for more than three months following an RT-PCR test confirming COVID-19 infection.

Participants were divided into two groups: 37 patients received HBOT treatment, while 36 patients served as a sham-controlled group, receiving placebo treatment. Both patients and investigators were unaware of their designated treatment protocol. The unique protocol consisted of 40 daily HBOT sessions, five sessions per week within a two-month period, in which patients entered a multi-place HBOT chamber and breathed 100% oxygen by mask at 2 atmospheres absolute (ATA) for 90 minutes with oxygen fluctuations. The control group received placebo treatment, breathing normal air. In addition, all participants underwent a computerized cognitive test, as well as advanced high-resolution brain imaging (profusion MRI and DTI) at two points in time – when entering the trial and after its completion.

 

Improved cerebral blood flow by HBOT in patient suffering from post-COVID symptoms (photo:  Sagol Center for Hyperbaric Medicine)

Repairing through Regeneration

The results were highly encouraging: patients treated with HBOT showed significant improvement, while in the control group long COVID symptoms remained largely unchanged.

In HBOT-treated patients, the greatest improvements were exhibited in the global cognitive function, attention, and executive functions (the capacity to plan, organize, initiate, self-monitor and control one’s responses to achieve a goal). Other benefits included better information processing speed, improved psychiatric symptoms, more mental energy, better sleep quality, and less body pain.

All clinical findings were correlated with the participants’ brain images, indicating significant change in the parts of the brain related to each function, which had been visibly damaged by the COVID-19 virus.

Dr. Shani-Itskovich Zilberman: “We know that HBOT repairs brain damage through a process of regeneration – generating new neurons and blood vessels. We believe that the beneficial effects of the unique treatment protocol in this study can be attributed to renewed neuroplasticity and increased brain perfusion in regions associated with cognitive and emotional roles.”

Prof. Efrati: “For the first time, our study proposes an effective treatment for the debilitating long COVID syndrome, repairing brain injury with an intensive protocol of HBOT. Moreover, the study reveals the very real biological damage to brain tissues induced by the COVID-19 virus, and how repairing this damage reduces symptoms and can eventually lead to recovery.”

“From a broader perspective, these findings can also suggest that other neurological and psychiatric syndromes might be triggered by biological agents such as viruses, opening new possibilities for future treatments.” 

Note: For patients with long COVID and other neurological disorders, reliable high-quality HBOT is now available at Aviv Clinics in Florida and Dubai, international arms of the Sagol Center at Shamir Medical Center (Assaf Harofeh) in Israel – administering the same strict protocols, with additional cognitive, physical and nutrition support provided to patients.

4th Covid-19 Vaccine Reduces Risk of Death by 72% Amongst Elderly

Study by Tel Aviv University, Ben Gurion University, and Israeli Ministry of Health included 40K Israelis.

A new study by Tel Aviv University and Ben Gurion University of the Negev, in collaboration with the Israeli Ministry of Health, found that the fourth COVID-19 vaccine is effective in protecting the elderly from the Omicron variant.

The groundbreaking study included approximately 40,000 elderly Israelis living in institutions supervised by the Ministry of Health’s “Senior Shield” program, a task force launched by Israel’s government to oversee the prevention and control of COVID-19 in the country’s geriatric facilities. According to its results, elderly at-risk individuals vaccinated with the fourth dose of the Pfizer vaccine have a 34% reduced risk of contracting the Omicron variant, a 64-67% reduced risk of requiring hospitalization due to COVID, and a 72% reduced risk of death from the virus.

The study was led by Prof. Khitam Muhsen and Prof. Dani Cohen of the School of Public Health at Tel Aviv University, Prof. Ron Dagan of Ben Gurion University, Prof. Nimrod Maimon, director of the Internal Medicine Department at Soroka Medical Center and until recently head of the Ministry of Health’s Senior Shield program, as well as program staff members Ami Mizrahi, Omri Bodenheimer, and Boris Boltyansky, in collaboration with Lea Gaon and Zafrira Hillel-Diamant of the Ministry’s Department of Geriatrics. The study was published in the prestigious journal JAMA Internal Medicine.

Particularly Vulnerable Population

“Our study compared 24,088 residents of Senior Shield facilities who received a fourth dose of the Pfizer vaccine – that is, the second booster shot – with 19,687 residents who were vaccinated with the first three doses four months or more prior to the follow-up, but who chose not to get the second booster,” explains Prof. Muhsen.

“These are residents of geriatric institutions, nursing homes and assisted living facilities that are part of the Ministry of Health’s Senior Shield system – a total of about 1,000 institutions across the country. This population is particularly vulnerable to infection, morbidity, and mortality from the coronavirus, due to the nature and living conditions of the institutions, the fact that many residents need help with daily activities, and the previous health issues that many of the residents suffer from.”

When the Omicron wave spread throughout Israel between January and March of this year, there was no registered and available vaccine for this variant, which underwent significant mutations in the spike protein that allows the virus to attach to and penetrate human cells. Because the existing COVID-19 vaccines target the spike protein, there has been much discussion in Israel and the rest of the world about the effectiveness of existing vaccines against the Omicron variant in general, and with regards to a second booster shot. Israel was the first country to approve the second booster (the fourth dose of the vaccine) for those aged 60 and above. The present study is based on data from the Senior Shield population database, which constituted the first large group to receive the second booster. Prof. Muhsen points out that this new study was conducted on a national scale, and that it successfully addressed the methodological problems that characterize observational epidemiological studies on the effectiveness of COVID vaccines.

Fourth Dose Saved Many Lives

“We monitored the infections, hospitalizations and mortality rates in these two groups throughout the Omicron wave, and found that the members of the group that received the fourth vaccine were infected at a rate that was 34% less than the control group; were hospitalized for mild-to-moderate illness 64% less, and for severe illness 67% less than the control group; and had a mortality rate that was 72% less than the group vaccinated with only the first three doses,” says Prof. Muhsen.

“These are significant data, because the Senior Shield population is one of the groups who suffer the most severe morbidity from the coronavirus, at a much higher rate than the general population. We assume that the fourth dose of the vaccine boosted the level of neutralizing antibodies, which conferred cross-protection against the Omicron variant. Our study points to the significant benefit of administering the fourth dose of the vaccine and confirms that the policy adopted by the State of Israel was the correct one. The decision to vaccinate at-risk populations with the fourth dose was a wise choice that saved a lot of human lives.”

Prof. Muhsen adds: “This is a groundbreaking and innovative study based on a database of the elderly population in care facilities. Previous studies have been conducted in the general population, and therefore also among relatively young populations with an average age of around 72, whereas the average age in our study was 80. Moreover, in general, people who go to be tested or vaccinated against COVID tend to exhibit positive health behaviors, so it is very difficult to compare their morbidity levels to those of unvaccinated people or those who have been vaccinated with three doses. We have no information as to why some of the residents chose not to receive the fourth vaccine dose, but both groups in our study underwent routine and ‘blind’ COVID tests according to uniform Senior Shield protocol, regardless of whether they received the vaccine. Therefore, our study was less affected by the ‘healthy vaccinee effect,’ and its results can also be applied to other populations, in Israel and around the world.”

According to Prof. Dani Cohen, “The study indicates that giving booster shots and raising the level of antibodies through a vaccine based on the original COVID-19 strain provides significant protection against the onset of serious illness even after infection with new variants, including those that are very different from the original, such as Omicron.”

Prof. Nimrod Maimon adds that “The task of protecting institutions for people living outside of the home is a very important aspect of the Ministry of Health’s Senior Shield program. The database that the project has built and accumulated about the institutions and their residents has allowed for rapid and effective vaccination campaigns, which have yielded dramatic results in curbing illness from the coronavirus amongst these populations. The impressive results of the program have received widespread international praise, with health authorities from many countries around the world seeking to learn from the Senior Shield program.”

Prof. Ron Dagan concludes that the results presented in the study demonstrate once again the critical role of vaccines and the use of structured and effective systems in curbing waves of severe morbidity and mortality in at-risk populations.

Going to the Beach? Sun Exposure Makes Men Hungrier than Women

TAU researchers find surprising connection between sun exposure and men’s appetite.

A new study from Tel Aviv University reveals that solar exposure increases appetite in males, but not in females. It is the first gender-dependent medical study ever conducted on UV exposure, and for the first time, the molecular connection between UV exposure and appetite was deciphered.

Skin as Regulator of Appetite

The groundbreaking study was led by Prof. Carmit Levy and PhD student Shivang Parikh of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler Faculty of Medicine. It was conducted in collaboration with many researchers in Israel and worldwide, including contributors from Tel Aviv Sourasky (Ichilov), Assuta, Meir, and Sheba Medical Centers, along with Dr. Yiftach Gepner and Dr. Lior Bikovski from TAU’s Sackler Faculty of Medicine, and Prof. Aron Weller of Bar-Ilan University. The paper was published in the prestigious journal Nature Metabolism.

The study was based on epidemiological data collected in a year-long survey about the eating habits of approximately 3,000 Israelis of both sexes, including self-reports from students who had spent time in the sun, combined with the results of a genetic study in a lab model. The findings identify the skin as a primary regulator of energy and appetite (metabolism) in both lab models and humans.

 

Prof. Carmit Levy

Estrogen Hormone Blocks Urge to Eat in Women

The study unravels the differences between males and females in the activation of the metabolic mechanism. The researchers explain that in males of both animal species and humans, sun exposure activates a protein called p53, to repair any DNA damage in the skin that might have been caused by the exposure. The activation of p53 signals the body to produce a hormone called ghrelin, which stimulates the appetite.

In females, the hormone estrogen blocks the interaction between p53 and ghrelin, and consequently does not catalyze the urge to eat following exposure to the sun.

The researchers explain that there is a dramatic metabolic difference between males and females, impacting both their health and their behavior. However, so far it has not been established whether the two sexes respond differently to environmental triggers such as exposures to the sun’s UV radiation.

“We examined the differences between men and women after sun exposure and found that men eat more than women because their appetite has increased. Our study was the first gender-dependent medical study ever conducted on UV exposure, and for the first time, the molecular connection between UV exposure and appetite was deciphered. Gender-dependent medical studies are particularly complex, since twice the number of participants is required to find statistically significant differences,” explains Prof. Levy.

“As humans, we have cast off our fur and consequently, our skin, the largest organ in our body, is exposed to signals from the environment. The protein p53, found in the skin, repairs damage to the DNA caused by sun exposure, but it does more than that. It signals to our bodies that winter is over, and we are out in the sun, possibly in preparation for the mating season. Our results provide an encouraging basis for more research, on both human metabolism and potential UV-based therapies for metabolic diseases and appetite disorders,” Prof. Levy concludes.

While You Were Sleeping

Could we be one step closer to verifying whether a seemingly unconscious person is truly unaware of his or her surroundings?

A new TAU discovery may provide a key to a great scientific enigma: How does the awake brain transform sensory input into a conscious experience? The researchers were surprised to discover that the brain’s response to sound remains powerful during sleep in all parameters but one: the level of alpha-beta waves associated with attention to the auditory input and related expectations. This means that during sleep, the brain analyzes the auditory input but is unable to focus on the sound or identify it, and therefore no conscious awareness ensues.

The study was led by Dr. Hanna Hayat and with major contribution from Dr. Amit Marmelshtein, at the lab of Prof. Yuval Nir from the School of Medicine of the Sackler Faculty of Medicine, the Sagol School of Neuroscience, and the Department of Biomedical Engineering, and co-supervised by Prof. Itzhak Fried from the UCLA Medical Center. Other participants included: Dr. Aaron Krom and Dr. Yaniv Sela from Prof. Nir’s group, and Dr. Ido Strauss and Dr. Firas Fahoum from the Tel Aviv Sourasky Medical Center (Ichilov). The paper was published in the prestigious journal Nature Neuroscience.

A Deep Dive into the Human Brain

Prof. Nir explains that this study is unique in that it builds upon rare data from electrodes implanted deep inside the human brain, enabling high-resolution monitoring, down to the level of individual neurons, of the brain’s electrical activity.

While electrodes cannot be implanted in the brain of living humans just for the sake of scientific research, in this case the researchers were able to utilize a special medical procedure in which electrodes were implanted in the brains of epilepsy patients, monitoring activity in different parts of their brain for purposes of diagnosis and treatment. The patients volunteered to help examine the brain’s response to auditory stimulation in wakefulness versus sleep.

The researchers placed speakers emitting various sounds at the patients’ bedside and compared data from the implanted electrodes – neural activity and electrical waves in different areas of the brain – during wakefulness and during various stages of sleep. Altogether, the team collected data from over 700 neurons (about 50 neurons in each patient) over the course of 8 years.

 

Dr. Hanna Hayat

Measuring the Strength of Alpha-beta Waves

“After sounds are received in the ear, the signals are relayed from one station to the next within the brain,” explains Dr. Hayat. “Until recently it was believed that during sleep these signals decay rapidly once they reach the cerebral cortex.  But looking at the data from the electrodes, we were surprised to discover that the brain’s response during sleep was much stronger and richer than we had expected. Moreover, this powerful response spread to many regions of the cerebral cortex. The strength of brain response during sleep was similar to the response observed during wakefulness, in all but one specific feature: the level of activity of alpha-beta waves.”

The researchers explain that alpha-beta waves (10-30Hz) are linked to processes of attention and expectation that are controlled by feedback from higher regions in the brain. As signals travel ‘bottom-up’ from the sensory organs to higher regions, a ‘top-down’ motion also occurs: the higher regions, relying on prior information that had accumulated in the brain, act as a guide, sending down signals to instruct the sensory regions as to which input to focus on, which should be ignored, etc. Thus, for example, when a certain sound is received in the ear, the higher regions can tell whether it is new or familiar, and whether it deserves attention or not.

“We hope that our findings will serve as a basis for developing effective new methods for measuring the level of awareness of individuals who are supposedly in various states of unconsciousness.”

This kind of brain activity is manifested in the suppression of alpha-beta waves, and indeed, previous studies have shown a high level of these waves in states of rest and anesthesia. According to the current study, the strength of alpha-beta waves is the main difference between the brain’s response to auditory inputs in states of wakefulness vs. sleep.

Decoding Consciousness

Prof Nir summarizes: “Our findings have wide implications beyond this specific experiment. First, they provide an important key to an ancient, fascinating enigma: What is the secret of consciousness? What is the ‘X-factor’, the brain activity that is unique to consciousness, allowing us to be aware of things happening around us when we are awake, and disappearing when we sleep? In this study we discovered a new lead, and in future research we intend to further explore the mechanisms responsible for this difference. 

“In addition, having identified a specific brain feature that is different between states of consciousness and unconsciousness, we now have a distinct quantitative measure – the first of its kind – for assessing an individual’s awareness of incoming sounds. We hope that in the future, with improved techniques for measuring alpha-beta brain waves, and non-invasive monitoring methods such as EEG, it will be possible to accurately assess a person’s state of consciousness in various situations: verifying that patients remain unconscious throughout a surgical procedure, monitoring the awareness of people with dementia, or determining whether an allegedly comatose individual, unable to communicate, is truly unaware of his/her surroundings. In such cases, low levels of alpha-beta waves in response to sound could suggest that a person considered unconscious may in fact perceive and understand the words being said around him. We hope that our findings will serve as a basis for developing effective new methods for measuring the level of awareness of individuals who are supposedly in various states of unconsciousness. “

 

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