TAU NEWS – Medicine & Health
Lack of vitamin has long-term consequences for children's health, TAU researchers say
A new Tel Aviv University study published in Maternal and Child Nutrition found that infantile Vitamin B1 (thiamine) deficiency severely affected the motor function of preschoolers who were fed faulty formula in the first year of their lives. The conclusions were based on a retrospective study of children who received Remedia, an Israeli formula brand completely lacking in Vitamin B1, in 2004.
The study was conducted by Prof. Aviva Fattal-Valevski of TAU's Sackler School of Medicine and the director of the Pediatric Neurology Unit at Tel Aviv Sourasky Medical Center, and her master's student Yael Harel.
Prof. Fattal-Valevski followed the development of 39 five- to six-year-old children who had been exposed to a thiamine-deficient formula as infants. She compared their motor performance with 30 age-matched healthy children with unremarkable infant nutritional history.
The participants' motor function was evaluated with the Movement Assessment Battery for Children and the Zuk Assessment. Both tests revealed statistically significant differences between the exposed and unexposed groups for gross and fine motor development. The differences were especially noteworthy with regards to balance-control functioning and fine motor skills. Both assessments concurred on the high rate of children exhibiting motor function difficulties in comparison to the unexposed group.
Continuing effects of vitamin deficiency in infancy
Infant deaths caused 13 years ago by the Remedia formula brand in Israel brought to light the potentially devastating impact of vitamin B1 deficiency. The infants were hospitalized with cardiac and neurological symptoms caused by the lack of vitamin B1, which is usually found in their formula.
"At first it was a mystery," said Prof. Fattal-Valevski. "It was like an epidemic. But after the grandmothers discussed the situation in the waiting room, it became clear that the infants, all under a year old, had consumed the same formula.
"After a food technician from the Health Department confirmed the total lack of vitamin B1 in the formula, we immediately provided the infants with supplements. Some recovered quickly, but three infants died and about 20 infants were left with severe disabilities and epilepsy."
The need for awareness
"The body's capacity for storing Vitamin B1 is limited," said Prof. Fattal-Valevski. "Unlike vitamin B12, vitamin B1 is only stored in the body for three weeks. It needs to be frequently replenished. It is critical to be aware of how important this vitamin is for child development. Even healthy babies might be at risk for B1 deficiency. If your infant is suffering from virus after virus, you must intervene with extra vitamins. But it's a vicious cycle, because one of the first symptoms of lack of B1 in the system is an absence of appetite.
"We've proven that B1 deficiency in infancy has long-term implications on gross and fine motor function and balance skills in childhood," said Prof. Fattal-Valevski. "Our study emphasizes the importance of proper infant feeding and regulatory control of breast milk substitutes."
The researchers are now focused on the link between infant B1 deficiency and later learning disabilities.
Modifying specific proteins during cancer cell division unleashes a natural killing mechanism, say TAU researchers
Many cancer patients struggle with the adverse effects of chemotherapy, still the most prescribed cancer treatment. For patients with pancreatic cancer and other aggressive cancers, the forecast is more grim: there is no known effective therapy.
A new Tel Aviv University study published last month in Oncotarget discloses the role of three proteins in killing fast-duplicating cancer cells while they're dividing. The research, led by Prof. Malka Cohen-Armon of TAU's Sackler School of Medicine, finds that these proteins can be specifically modified during the division process — mitosis — to unleash an inherent "death mechanism" that self-eradicates duplicating cancer cells.
"The discovery of an exclusive mechanism that kills cancer cells without impairing healthy cells, and the fact that this mechanism works on a variety of rapidly proliferating human cancer cells, is very exciting," Prof. Cohen-Armon said. "According to the mechanism we discovered, the faster cancer cells proliferate, the faster and more efficiently they will be eradicated. The mechanism unleashed during mitosis may be suitable for treating aggressive cancers that are unaffected by traditional chemotherapy.
"Our experiments in cell cultures tested a variety of incurable human cancer types — breast, lung, ovary, colon, pancreas, blood, brain," Prof. Cohen-Armon continued. "This discovery impacts existing cancer research by identifying a new specific target mechanism that exclusively and rapidly eradicates cancer cells without damaging normally proliferating human cells."
The research was conducted in collaboration with Prof. Shai Izraeli and Dr. Talia Golan of the Cancer Research Center at Sheba Medical Center, Tel Hashomer, and Prof. Tamar Peretz, head of the Sharett Institute of Oncology at Hadassah Medical Center, Ein Kerem.
A new target for cancer research
The newly-discovered mechanism involves the modification of specific proteins that affect the construction and stability of the spindle, the microtubular structure that prepares duplicated chromosomes for segregation into "daughter" cells during cell division.
The researchers found that certain compounds called Phenanthridine derivatives were able to impair the activity of these proteins, which can distort the spindle structure and prevent the segregation of chromosomes. Once the proteins were modified, the cell was prevented from splitting, and this induced the cell's rapid self-destruction.
"The mechanism we identified during the mitosis of cancer cells is specifically targeted by the Phenanthridine derivatives we tested," Prof. Cohen-Armon said. "However, a variety of additional drugs that also modify these specific proteins may now be developed for cancer cell self-destruction during cell division. The faster the cancer cells proliferate, the more quickly they are expected to die."
Research was conducted using both cancer cell cultures and mice transplanted with human cancer cells. The scientists harnessed biochemical, molecular biology and imaging technologies to observe the mechanism in real time. In addition, mice transplanted with triple negative breast cancer cells, currently resistant to available therapies, revealed the arrest of tumor growth.
"Identifying the mechanism and showing its relevance in treating developed tumors opens new avenues for the eradication of rapidly developing aggressive cancers without damaging healthy tissues," said Prof. Cohen-Armon.
The researchers are currently investigating the potential of one of the Phenanthridine derivatives to treat two aggressive cancers known to be unresponsive to current chemotherapy: pancreatic cancer and triple negative breast cancer.
Executive function and memory are particularly vulnerable to the effects of insulin resistance, TAU researchers say
A new Tel Aviv University study published in the Journal of Alzheimer's Disease finds that insulin resistance, caused in part by obesity and physical inactivity, is also linked to a more rapid decline in cognitive performance. According to the research, both diabetic and non-diabetic subjects with insulin resistance experienced accelerated cognitive decline in executive function and memory.
The study was led jointly by Prof. David Tanne and Prof. Uri Goldbourt and conducted by Dr. Miri Lutski, all of TAU's Sackler School of Medicine.
"These are exciting findings because they may help to identify a group of individuals at increased risk of cognitive decline and dementia in older age," says Prof. Tanne. "We know that insulin resistance can be prevented and treated by lifestyle changes and certain insulin-sensitizing drugs. Exercising, maintaining a balanced and healthy diet, and watching your weight will help you prevent insulin resistance and, as a result, protect your brain as you get older."
A two-decade study
Insulin resistance is a condition in which cells fail to respond normally to the hormone insulin. The resistance prevents muscle, fat, and liver cells from easily absorbing glucose. As a result, the body requires higher levels of insulin to usher glucose into its cells. Without sufficient insulin, excess glucose builds up in the bloodstream, leading to prediabetes, diabetes, and other serious health disorders.
The scientists followed a group of nearly 500 patients with existing cardiovascular disease for more than two decades. They first assessed the patients' baseline insulin resistance using the homeostasis model assessment (HOMA), calculated using fasting blood glucose and fasting insulin levels. Cognitive functions were assessed with a computerized battery of tests that examined memory, executive function, visual spatial processing, and attention. The follow-up assessments were conducted 15 years after the start of the study, then again five years after that.
The study found that individuals who placed in the top quarter of the HOMA index were at an increased risk for poor cognitive performance and accelerated cognitive decline compared to those in the remaining three-quarters of the HOMA index. Adjusting for established cardiovascular risk factors and potentially confounding factors did not diminish these associations.
"This study lends support for more research to test the cognitive benefits of interventions such as exercise, diet, and medications that improve insulin resistance in order to prevent dementia," says Prof. Tanne. The team is currently studying the vascular and non-vascular mechanisms by which insulin resistance may affect cognition.
Challenge-based intervention may be effective in reducing the severity of autism symptoms, TAU researchers say
A new Tel Aviv University study finds outdoor challenge-based interventions may be effective in reducing the overall severity of Autism Spectrum Disorder (ASD) symptoms. The research found significant improvements in the social cognition, social motivation, and autistic mannerisms of the young subjects after outdoor adventure activities and describes a new path for enhancing the social and communication skills of children with ASD.
The study was published in Developmental Medicine and Child Neurology and led by Prof. Ditza Antebi-Zachor of the Pediatric Department at TAU's Sackler Faculty of Medicine and Director of Assaf Harofeh Medical Center's Autism Center, together with Prof. Esther Ben Itzchak of Ariel University.
One in 68 children in the US is diagnosed each year with ASD, a neurodevelopmental disorder characterized by socio-communicative impairments and restricted and repetitive behaviors and interests. The developmental disorder takes a deep social, emotional and economic toll on the child and his/her family. But research has also shown that the early diagnosis and early treatment of ASD can lead to vast improvements in the cognitive functioning and socio-communicative skills of children on the spectrum.
Getting out of the classroom
Fifty-one children from seven special-education kindergartens in Tel Aviv participated in the study, which was conducted in collaboration with ALUT, the National Israeli Association for Children with Autism, and ETGARIM, a nonprofit that sponsors outdoor activities for disabled people. The children, aged 3-7, all followed the same educational protocols, but the intervention group, comprising 30 students, also participated in an outdoor adventure program (OAP).
The intervention group underwent 13 weekly sessions of challenge-based activities with instructors. Each 30-minute session took place in urban parks near the participants' kindergartens and kicked off with a song. Afterward, the children used the outdoor fitness equipment, moving from one to another throughout the session. The activities required the children to communicate with the instructors and with their peers, to ask for assistance or be noticed, for example.
Prior to the adventure program, the children's cognitive and adaptive skills were assessed by the kindergarten instructors using the Social Responsiveness Scale (SRS), a questionnaire that assesses autism severity in different domains, and the Teachers' Perceived Future Capabilities questionnaire. The information was obtained prior to and after completing the program.
Meeting goals and building trust
"Outdoor adventure programs are designed to improve intrapersonal skills and interpersonal relationships by using adventurous activities to provide individual and group problem-solving and challenge tasks," says Prof. Zachor. "The necessary tools for a successful OAP include establishing individual and group goals, building trust among participants, and providing activities that challenge and evoke stress but are nevertheless enjoyable.
"Our study shows that outdoor adventure activities benefit children with autism and improve their social communication skills. We suggest including these fun activities in special education kindergartens and in communication classrooms at school in addition to traditional treatments. Parents of children with ASD can also enroll their kids in afterschool activities based on the principles of our research. It will allow the children to have fun during their leisure time while improving their communication skills."
According to Prof. Zachor, future studies should examine the contribution of this type of intervention over longer periods of time and encourage other researchers to explore new treatments that improve social communication skills in an entertaining, engaging way. “We're interested in studying the long-term effect of this intervention, not just on ASD symptoms but on functioning in different domains, including behavioral problems, language skills, and attention span," she says.
NAP blocks formation of "tangles" that contribute to Alzheimer's disease, says TAU researcher
Tau is a key brain protein involved in Alzheimer's disease and other brain diseases. Aggregates of Tau known as "neurofibrillary tangles" have been associated with nerve cell death and cognitive decline.
An important new Tel Aviv University study published in Molecular Psychiatry pinpoints the mechanism harnessed by the drug candidate NAP to block the formation of these harmful neurofibrillary tangles. It facilitates the interaction of Tau with microtubules, the minitubes that serve as "train tracks" for essential movement of biological material in nerve cells.
"Abnormal Tau proteins form tangles that contribute to the progression of Alzheimer's disease," said Prof. Illana Gozes, who led the research for the study. "We showed here, for the first time, that the drug candidate NAP augmented microtubule movement in nerve cells. At the molecular level, NAP, a fragment of activity-dependent neuroprotective protein (ADNP), enhanced Tau-microtubule interactions that block the recruitment of Tau to the tangles observed in Alzheimer's disease and related disorders."
Prof. Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Sackler Faculty of Medicine and a member of TAU's Adams Super Center for Brain Studies and the Sagol School of Neuroscience.
Stabilizing a neurobiological process
Prof. Gozes is responsible for discovering ADNP, a gene that is dysregulated in Alzheimer's. Mutations in ADNP that occur in pregnancy are a major cause of autism with intellectual disability.
"ADNP and NAP operate through the stabilization of microtubules — tubes within the cell that maintain cellular shape," Prof. Gozes said. "They transport biological material. These microtubules break down in in Alzheimer's disease and may be dysfunctional in autism. NAP works to protect the microtubules, thereby protecting the cell."
"We now discovered that ADNP dramatically enhances Tau binding to the microtubules, protecting them against destruction and against Tau pathology. We further discovered that this action of ADNP is through its NAP fragment, which is now intended for further clinical development."
"Knowing the precise mechanism of its action, it will be much easier to bring NAP to the clinic and to patients," said Prof. Gozes. "Furthermore, the precise mechanism defines a new drug target for autism spectrum disorders, Alzheimer's disease and many other neurodegenerative and neuropsychiatric diseases."
The research for the study was conducted by TAU graduate students Yanina Ivashko-Pachima and Dr. Anna Malishkevich, together with Dr. Laura C. Sayas of Centro de Investigaciones Biomédicas de Canarias. NAP (now called CP201), a Tel Aviv University technology under a term sheet agreement with Coronis Neurosciences, is now planned for future clinical trials in patients with autism, specifically those with ADNP-related syndrome.
Familial Dysautonomia may be slowed by phosphatidylserine, TAU researchers say
A new Tel Aviv University study finds that a popular food supplement called phosphatidylserine may be instrumental in reversing the detrimental effects of Familial Dysautonomia (FD), a debilitating neurodegenerative disorder that affects approximately 1 in 31 Jewish people of Eastern European, or Ashkenazi, ancestry. FD affects aspects of the autonomic nervous system such as swallowing, sweating, and pain sensitivity, and places patients at increased risk for pulmonary and gastrointestinal complications.
The research, led jointly by Prof. Gil Ast and Prof. Eran Perlson of TAU's Sackler School of Medicine, generated a mouse model of FD to examine the neuron degeneration caused by FD and to observe the positive effects of the novel therapy. The study was published in PLOS Genetics.
Trucks, highways, and neurons
"Neurons are the longest cells in our body," said Prof. Ast. "'Highways' along our neurons allow 'trucks' with 'cargo' to supply our neurons with essential supplies. In most neurodegenerative diseases these highways — called microtubules — and the axonal transport process are impaired. Our study demonstrates that alterations in the stability of microtubules and disruptions in the transport may lead to FD."
The research team, including Shiran Naftelberg-Blonder and other TAU students, generated a mouse model of FD. The mice exhibited symptoms similar to those experienced by human patients with FD, including developmental delays, sensory abnormalities, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor.
"We found that in neurons from our FD mice, the microtubular highways were impaired by elevated levels of an enzyme called HDAC6," said Prof. Ast. "This impairment removed the adhesive that connects the 'bricks' of the highway. This led to less stabilized highways and to the slower movement of cargo along it."
Once the mouse exhibiting FD symptoms was generated, the researchers administered a phosphatidylserine treatment, which lowered the level of the enzyme that removed the "glue" from the "bricks" of the microtubular highways. Phosphatidylserine contains both amino acids and fatty acids and is known to be effective in slowing down long-term memory loss.
Finding a "path" to treatment
The researchers found that the treatment with phosphatidylserine enhanced the stability of the microtubular "highways" and improved the movement of "cargo" along these pathways. "We identified the molecular pathway that leads to neurodegeneration in FD and demonstrated that phosphatidylserine has the potential to slow progression of neurodegeneration," said Prof. Ast.
"Phosphatidylserine can repair the activity in neurons from the FD mouse by reducing the amount of the enzyme that removes the 'glue' from the 'bricks,'" Prof. Ast continued. "This elevates the stability of the 'highways' and increases essential cargo movement along these neurological pathways."
The researchers are currently researching ways of improving the delivery of phosphatidylserine to the nervous system. Teva Pharmaceuticals contributed support for this research through the National Network of Excellence.
TAU study finds famine may have a lasting impact on male descendants of its victims
New Tel Aviv University research suggests that periods of fasting or starvation may significantly shorten the lifespans of both children and their male descendants.
The study focused on survivors of a mass famine that took place in the early 1920s in several rural regions of Russia. It was led by Prof. Eugene Kobyliansky of TAU's Sackler School of Medicine and conducted by doctoral student Dmitry Torchinsky of TAU's Raymond and Beverly Sackler Faculty of Exact Sciences, in collaboration with Dr. Leonid Kalichman of Ben-Gurion University's Department of Physical Therapy and Prof. David Karasik of Bar Ilan University's Faculty of Medicine in the Galilee. Its conclusions were published in The American Journal of Clinical Nutrition.
"A variety of experimental and epidemiological studies have tried to propose that intermittent or periodic fasting, like caloric restriction, may slow the aging process and extend lifespans," said Prof. Kobyliansky. "But there is also evidence demonstrating that even moderate caloric restriction may not extend but, on the contrary, can shorten the human lifespan."
A lesson from Russia
Past research suggests a strong correlation between telomere dynamics and the processes that determine human aging and lifespan. Telomeres, compound structures at the end of each chromosome that protects the end of the chromosome from deterioration, are the genetic key to longevity. They shorten with every chromosome replication cycle.
The team evaluated telomere lengths in a population–based sample comprised of survivors of the mass famine of the early 1920s and in the survivors' descendants, who originated from Chuvashia, a rural area in the mid-Volga region of Russia. In Chuvashia, the proportion of starving inhabitants reached 90% in late March 1922, and mortality among starving peasants reached between 30-50%. The situation only began to improve in April 1923. By the end of that year, the mass famine in Chuvashia was considered over.
The researchers arrived at three major discoveries: (1) There were shorter leukocyte telomeres in men born after 1923 after the mass famine ended than in men born before 1922; (2) there was a stable inheritance of shorter telomeres by men born in ensuing generations; and (3) there was an absence of any correlation between shorter telomeres and women born before or after the event.
"This study, while demonstrating that starvation has the potential to shorten telomere length, raises several questions," said Prof. Kobyliansky. "Does starvation exert a stronger effect on telomere length in the reproductive cells of adults than in the leukocytes of children? Is starvation-induced telomere shortening a sex-dependent phenomenon? And would fasting regimens exerting beneficial effects be accompanied by telomere shortening in descendants?"
The team is currently considering experimental in vivo studies to answer these and other questions.
Identification could lead to new diagnostic blood test and therapeutics, say TAU researchers
A new Tel Aviv University study identified a gene coding for a protein that turns off neurotransmission signaling, which contributes to Alzheimer's disease (AD).
The gene, called RGS2 (Regulator of Protein Signaling 2), has never before been implicated in AD. The researchers report that lower RGS2 expression in AD patient cells increases their sensitivity to toxic effects of amyloid-β. The study, published in Translational Psychiatry, may lead to new avenues for diagnosing Alzheimer's disease — possibly a blood test — and new therapies to halt the progression of the disease.
The research was led by Dr. David Gurwitz of the Department of Human Molecular Genetics and Biochemistry at TAU's Sackler School of Medicine and Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Sackler School of Medicine; and a member of TAU's Adams Super Center for Brain Studies and TAU's Sagol School of Neuroscience. Also participating in the research were their PhD student Adva Hadar and postgraduate student Dr. Elena Milanesi, in collaboration with Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU's Sackler Faculty of Medicine and his postgraduate student Dr. Daphna Weissglas; and research teams from Italy and the Czech Republic.
Identifying the suspect
"Alzheimer's researchers have until now zeroed in on two specific pathological hallmarks of the chronic neurodegenerative disease: deposits of misfolded amyloid-β (Aβ) peptide plaques, and phosphorylated tau protein neurofibrillary tangles found in diseased brains," Dr. Gurwitz said. "But recent studies suggest amyloid-β plaques are also a common feature of healthy older brains. This raises questions about the central role of Aβ peptides in Alzheimer's disease pathology."
The researchers pinpointed a common suspect — the RGS2 gene — by combining genome-wide gene expression profiling of Alzheimer's disease blood-derived cell lines with data-mining of previously published gene expression datasets. They found a reduced expression of RGS2 in Alzheimer's disease blood-derived cell lines, then validated the observation by examining datasets derived from blood samples and post-mortem brain tissue samples from Alzheimer's patients.
"Several genes and their protein products are already known to be implicated in Alzheimer's disease pathology, but RGS2 has never been studied in this context," Dr. Gurwitz said. "We now propose that whether or not Aβ is a primary culprit in Alzheimer's disease, neuroprotective mechanisms activated during early disease phases lead to reduced RGS2 expression."
Sensitizing brain neurons to potential damage
The new TAU study furthermore proposes that reduced RGS2 expression increases the susceptibility of brain neurons to the potentially damaging effects of Aβ.
"We found that reduced expression of RGS2 is already noticeable in blood cells during mild cognitive impairment, the earliest phase of Alzheimer's," Dr. Gurwitz observed. "This supported our theory that the reduced RGS2 expression represents a 'protective mechanism' triggered by ongoing brain neurodegeneration."
The team further found that the reduced expression of RGS2 was correlated with increased Aβ neurotoxicity. It acted like a double-edged sword, allowing the diseased brain to function with fewer neurons, while increasing damage to it by accumulating misfolded Aβ.
"Our new observations must now be corroborated by other research groups," Dr. Gurwitz concluded. "The next step will be to design early blood diagnostics and novel therapeutics to offset the negative effects of reduced expression of the RGS2 protein in the brain."
Combined Virtual Reality–Treadmill Training May Prevent Falls Associated with Parkinson’s and Other Disorders
Intervention can be used in gyms, rehabilitation centers and nursing homes, TAU researchers say
A combination of virtual reality and treadmill training may prove effective in preventing dangerous falls associated with aging, Parkinson's disease, mild cognitive impairment or dementia, according to a new Tel Aviv University–Tel Aviv Sourasky Medical Center (TASMC) study published in The Lancet.
According to the study's lead authors, Prof. Jeff Hausdorff and Dr. Anat Mirelman, both of TAU's Sackler School of Medicine and TASMC's Center for the Study of Movement, Cognition and Mobility, the intervention combines the physical and cognitive aspects of walking, and could be implemented in gyms, rehabilitation centers and nursing homes to improve walking skills and prevent the falls of older adults and those with movement disorders like Parkinson's disease.
"Falls often start a vicious cycle with many negative health consequences," said Dr. Mirelman. "The ability of older people to negotiate obstacles can be impaired because of age-related decline in cognitive abilities like motor planning, divided attention, executive control and judgement. But current interventions typically focus almost exclusively on improving muscle strength, balance and gait.
"Our approach helps improve both physical mobility and cognitive aspects that are important for safe walking," Dr. Mirelman continued. "We found that virtual reality plus treadmill training helped to reduce fall frequency and fall risk for at least six months after training — significantly more than treadmill training alone. This suggests that our use of virtual reality successfully targeted the cognitive aspects of safe ambulation to reduce the risk of falls."
Adding virtual reality to the therapeutic recipe
The TAU-TASMC team, in collaboration with partners across Europe, collected data from 282 participants at five clinical sites in Belgium, Israel, Italy, the Netherlands and the UK between 2013 and 2015. The participants, all aged 60-90, were able to walk at least five minutes unassisted, were on stable medications and, critically, had reported at least two falls in the six months prior to the start of the study. Nearly half of all participants (130) had Parkinson's disease, and some (43) had mild cognitive impairment.
Participants were assigned to treadmill training with virtual reality (146) or treadmill training alone (136). The virtual reality component consisted of a camera that captured the movement of participants' feet and projected it onto a screen in front of the treadmill, so that participants could "see" their feet walking on the screen in real time.
The game-like simulation was designed to reduce the risk of falls in older adults by including real life challenges such as avoiding and stepping over obstacles like puddles or hurdles, and navigating pathways. It also provided motivation to the participants, giving them feedback on their performance and scores on the game.
Greater satisfaction, more effective therapy
While the incident rate of falls was similar in the two groups prior to the intervention, six months after training the rate of falls among those who trained with VR dropped by almost 50%. In contrast, there was no significant reduction in the fall rates among subjects who did not train with the VR.
"Interestingly, when we asked people if they enjoyed the treatment program, participants in the virtual reality group reported higher scores on user satisfaction questionnaires and a greater desire to continue to exercise with the 'game,'" said Prof. Hausdorff. "This suggests that the virtual reality not only led to fewer falls, it was also more likely to be used in the long-term. Exercise needs to be fun and effective if it is going to be used continually.
"The biggest improvement was seen in participants with Parkinson's disease," Prof. Hausdorff continued. "It was very exciting to see such improvement in the presence of a neurodegenerative disease. Still, we need to conduct further research to verify the results and better understand why the fall rates were so responsive in the people with Parkinson's disease."
"Treadmills are widely available, and the additional cost of treadmill training plus virtual reality is only about $4,500. The low cost could permit this approach to be widely used in various settings," said Dr. Mirelman. "Future studies need to examine whether treadmill training plus virtual reality could be used as part of a prevention package to treat fall risk before falls become common and before injuries occur."
The research was funded by the European Commission.
APOE gene is a promising target for therapeutic approaches to Alzheimer's, says TAU researcher
For the last 20 years, researchers have focused on amyloid beta peptides and the "plaque" they sprout in diseased brains as the main target of Alzheimer's research. But the pace of progress in treating — not to mention curing — the debilitating, neurodegenerative disease has been painfully slow.
A Tel Aviv University study published last month in the Journal of Alzheimer's Disease suggests a new target for Alzheimer's research: the APOE gene. This gene, like Dr. Jekyll and Mr. Hyde, has two faces: a healthy form called APOE3 and a disease-related pathological form called APOE4. Researchers have developed a novel mechanism and approach with which to convert the "bad" APOE4 to the "good" APOE3.
The research was led by Prof. Daniel M. Michaelson, Director of the Eichenbaum Laboratory of Alzheimer's Disease Research and incumbent of the Myriam Lebach Chair in Molecular Neurodegeneration at TAU's Faculty of Life Sciences, together with Anat Boehm-Cagan, the Eleanore and Harold Foonberg Doctoral Fellow in Alzheimers Disease Research, and in collaboration with the commercial company Artery Ltd., based in California.
Focus on a new approach
"APOE4 is a very important and understudied target," Prof. Michaelson said. "It is expressed in more than 60 percent of Alzheimer's patients. Anti-APOE4 treatments are thus expected to have a major impact on the patient population.
"The normal APOE gene provides the interface that moves lipids — naturally occurring molecules that include fats, cholesterol, fat-soluble vitamins and other components essential to the health of cells — in and out of cells," Prof. Michaelson continued. "Whereas the healthy APOE3 does so effectively, the bad form — APOE4 — is impaired."
Prof. Michaelson and other groups found in past research that the bad APOE4 and the good APOE3 differed in their interactions with lipid cargo. The good APOE3, for example, is associated with substantially more lipids than APOE4.
The researchers devised an experimental approach to measure the "bad" features of APOE4, utilizing genetically manipulated mice expressing either good or bad forms of APOE. Mice with APOE4 exhibited impaired learning and memory, as well as damaged brain synapses and an accumulation of phosphorylated tau and a-beta molecules — two pathological hallmarks of Alzheimer's.
Turning a bad gene to good
"Once this model was established and the pathological effects of APOE4 could be reproduced in mice, we could test therapeutic approaches and tackle APOE4 itself," Prof. Michaelson said. "Because we know that APOE4 carries fewer lipids, we looked at the means of counteracting the lipidation deficiency.
"We focused on an enzymatic machinery called ABCA1 that loads lipid cargo onto APOE4. We found that the impaired lipidation of APOE4 could be successfully reversed by activating ABCA1. Most importantly, we discovered that this increased lipidation of APOE4 reversed the behavioral impairments and brain damage seen in non-treated APOE4 mice."
The researchers found in the course of administering treatment that mice, which prior to the treatment exhibited disoriented behavior and seemed "lost," were able following treatment to locate a submerged island in the middle of an artificial pond. Mice had forgotten familiar objects — like Coca Cola bottles — suddenly exhibited sharp object recognition.
"Is there really a magic bullet? One treatment that covers all aspects of Alzheimer's? Not likely," said Prof. Michaelson. "Therefore there is a need to define specific subpopulations and to develop treatments targeted at genetic risk factors of the disease, like APOE4, which affects more than half of the Alzheimer's population."
World-renowned neuroscientist and geneticist celebrated for "commitment to research and new therapies"
Tel Aviv University's Prof. Illana Gozes was awarded the 2016 RARE Champion of Hope — Science International Prize by Global Genes, a leading global advocacy non-profit organization for patients and families fighting rare and genetic diseases.
The ceremony took place at the 5th Annual Tribute to Champions of Hope presented by PRA Health Sciences on September 23 and 24 at the Huntington Beach Hyatt Resort and Spa in Aliso Viejo, CA. The annual blue carpet event honors and celebrates rare disease advocates, scientists, patients, and supporters.
Prof. Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Sackler Faculty of Medicine; and a member of TAU's Adams Super Center for Brain Studies and Sagol School of Neuroscience.
More than 350 individuals and organizations worldwide were nominated by members of the Global Genes Board of Directors and Medical and Science Advisory Board for their notable efforts in rare disease advocacy, science, collaborative sciences, and medical care and treatment. Only a few of the nominees were selected for the top honor.
A leader in genetic research
Prof. Gozes is a vanguard on the front of genetic research. She discovered the ADNP gene that causes the ADNP syndrome (also known as the Helsmoortal-Van Der AA syndrome), deregulates in Alzheimer's disease (AD) and in schizophrenia, and mutates in autism. Prof. Gozes has also been instrumental in drawing attention to the ways that ADNP binds to microtubules — tubes within nerve cells that maintain cell shape and serve as "train tracks" for movement of biological material through the brain.
"With her commitment to research and new therapies, Prof. Gozes continues to help many undiagnosed patients receive the therapies and tests needed to be happy, healthy, and diagnosed," according to Global Genes.
"There is no one else more worthy of receiving this award than Prof. Gozes," said Angela Downing, Chair of the ADNP Kids Research Foundation, who presented the award to Prof. Gozes. "She is a respected neuroscientist, a beloved professor and a mentor to many. She has worked tirelessly in her career not only for science but for humanity. Prof. Gozes delivers nothing but excellence in terms of research. Her commitment to our children, who suffer from ADNP disorders, is strong and we stand confident knowing she stands with us."
Sandra Sermone, Founder and President of the ADNP Kids Research Foundation, added: "I have known Prof. Gozes for the last two years, after my son was diagnosed with an ADNP mutation. She is a leader in ADNP research and drug development and works tirelessly to advance research and potential treatments for our children with this heart-breaking disease. She is committed, caring and compassionate. There is no one more deserving of an award associated with hope."
Praising a community
Global Genes is a leading global advocacy non-profit organization for patients and families fighting rare and genetic diseases. The organization hopes to find treatments and cures for the 7,000+ rare and genetic diseases that affect an estimated 30 million Americans and over 350 million people worldwide through building awareness, developing patient-focused educational tools, and funding patient care programs and early investigative research.
"I feel privileged to have helped this community," said Prof. Gozes. "I may have been able to help only a few families, but then they discussed the experience and passed on vital information to others in similar situations. Together, as a community, they have a voice which calls for more funding to support further critical research."
Together with Coronis Neurosciences (on agreement with Ramot@Tel Aviv University), Prof. Gozes is currently developing an ADNP-based drug for cognitive impairment in schizophrenia. A small fragment of ADNP called davunetide has shown promise in Phase IIa clinical trials, and Prof. Gozes is harnessing it for further advanced trials on large cohorts of patients. The exposure to the knowledgeable and compassionate community of Global Genes and the honor of receiving the RARE Champion of Hope — Science International Prize will no doubt accelerate drug development.
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TAU researchers discover physical mechanism that may enable immune system attack
Multiple sclerosis is one of the most devastating neurodegenerative diseases. It affects some 2.5 million people worldwide. It has no known cure.
Until now, researchers have speculated that the body's own immune system was unleashing an uncontrolled attack on myelin sheaths — our neurons' protective shield — that was largely responsible for the sudden outbreak of the disease.
But a new Tel Aviv University study published in the Journal of the American Chemical Society (JACS) pinpoints a structural instability in the myelin membranes, the "insulating tape" surrounding neurons. This vulnerability affords the immune system — and its attacks — access to otherwise protected regions.
"We found that small modifications in the myelin sheaths create structural instabilities that may help the immune system to enter and attack neurons," said Prof. Roy Beck, the study's principal investigator, of TAU's School of Physics and Astronomy and Sagol School of Neurosciences. "Current therapeutic approaches have focused on the autoimmune response without identifying a clear mechanism. Our research suggests a new avenue for multiple sclerosis therapies and diagnostics."
Breaking down the insulation
Our axons, which carry electrical impulses in neurons, are surrounded by protective myelin sheaths. In multiple sclerosis, an autoimmune catastrophe, these sheaths break down and are misidentified as hostile foreign entities, which the immune system then attacks.
The research, conducted by Rona Shaharabani, a doctoral student in Prof. Beck's lab, pinpoints the precise alterations to the myelin sheaths that result in structural instabilities, creating "easy access" for autoimmune attacks. "After years of research, we were amazed to discover that a possible trigger for the outbreak of the disease could be found in the membrane's physical structure," said Prof. Beck.
According to Prof. Beck, the lipid are the main building blocks of the myelin sheaths. As such their shape has a critical impact on the resulting self-assembled membrane structure. “If the basic building blocks are straight, the membrane will be flat, which is the preferred structure for a neuron's 'insulating tape,’" said Prof. Beck. "However, if they exhibit a more cone-like shape, the membrane will tend to form closed round cylinders. These produce spontaneous holes in the surface of the sheath, rendering it vulnerable to attack."
For the purpose of the research, the scientists harnessed X-ray light to examine hundreds of membrane model systems that mimicked those of healthy and diseased animal models. In collaboration with Prof. Ruth Arnon of the Weizmann Institute, co-developer of the leading MS drug Copaxone®, and Prof. Yeshayahu Talmon of the Technion – Israel Institute of Technology, the team also used electron microscopy to determine the different nanoscopic structures of both natural myelin sheaths and model system membranes.
"The next step is to find a way to reverse the disease progression and find new techniques for early detection," said Prof. Beck.
R. Shaharabani, M. Ram-On, R. Avinery, R. Aharoni, R. Arnon, Y. Talmon, R. Beck, Structural Transition in Myelin Membrane as Initiator of Multiple Sclerosis, Journal of the American Chemical Society (2016). http://pubs.acs.org/doi/abs/10.1021/jacs.6b04826
TAU researcher harnesses targeted delivery of microRNAs to primary tumors in mice to block the movement of cancer
A new Tel Aviv University study finds that combining genetic therapy with chemotherapy delivered to a primary tumor site is extremely effective in preventing breast cancer metastasis.
The research was led by Dr. Noam Shomron of TAU's Sackler School of Medicine in collaboration with Dr. Natalie Artzi of the Massachusetts Institute of Technology, and conducted by Dr. Shomron's students Avital Gilam and Dr. Daphna Weissglas and Dr. Artzi's student Dr. Joao Conde. Data on human genetics were provided by Prof. Eitan Friedman of TAU's Sackler Faculty of Medicine and Chaim Sheba Medical Center.
The research was published in the September 19, 2016, online issue of Nature Communications.
Stopping cancer at the turning point
One in eight women worldwide are diagnosed with breast cancer during their lifetimes. Breast cancer is the second leading cause of cancer death in women. The chance that a woman will die from breast cancer is about 1 in 36. Early detection, while increasingly common, is not sufficient to preventing metastasis, the lethal movement of cancerous cells from a primary tumor site to colonies in vital organs. About 80 percent of women with metastatic cancer die from the disease within just five years of being diagnosed.
"The situation is bleak. Death rates from breast cancer remain high and relatively unchanged despite advances in medicine and technology," said Dr. Shomron. "We wanted to find a way to stop metastasis from happening altogether. It's the turning point, where survival rates drop exponentially.
"Our mission was to block a cancer cell's ability to change shape and move. Cancer cells alter their cytoskeleton structure in order to squeeze past other cells, enter blood vessels and ride along to their next stop: the lungs, the brain or other vital organs. We chose microRNAs as our naturally-occurring therapy, because they are master regulators of gene expression."
Database, drugs and delivery
The researchers based their approach on the "3Ds" — database, drugs and delivery. The team began by exploring bioinformatics databases to investigate the span of mutations in a tumor and identify precisely which ones to target. The scientists then procured a naturally-occurring, RNA-based drug to control cell movement and created a safe nanovehicle with which to deliver the microRNA to the tumor site.
"We looked at mutations and polymorphisms that other researchers have ignored," said Dr. Shomron. "Mutations in the three prime untranslated regions (UTRs) at the tail end of a gene are usually ignored because they aren't situated within the coding region of the gene. We looked at the three UTR sites that play regulatory roles and noticed that mutations there were involved in metastasis."
Two weeks after initiating cancer in the breasts of their mouse "patients," the researchers injected into primary tumor sites a hydrogel that contained naturally occurring RNAs to target the movement of cancer cells from primary to secondary sites. Two days after this treatment, the primary breast tumors were excised.
The mice were evaluated three weeks later using CT imaging, flourescent labelling, biopsies and pathology. The researchers discovered that the mice that had been treated with two different microRNAs had very few or no metastatic sites, whereas the control group — injected with random scrambled RNAs — exhibited a fatal proliferation of metastatic sites.
From mice to humans
"We realized we had stopped breast cancer metastasis in a mouse model, and that these results might be applicable to humans," said Dr. Shomron. "There is a strong correlation between the effect on the genes in mouse cells and the effect on the genes in human cells. Our results are especially encouraging because they have been repeated several times at TAU and at MIT by independent groups."
The researchers are continuing their study of the effects of microRNAs on tumors within different microenvironments.
Watch Prof. Shomron’s TEDx talk about his research: https://www.youtube.com/watch?v=wAoZym_anr0
Natural and induced deliveries following amniotic sac rupture share similar neonatal outcomes
A new Tel Aviv University study has determined that natural, spontaneous deliveries and induced deliveries following the rupture of the amniotic sac in the mother share similar neonatal outcomes, contradicting common wisdom.
"Induced labor — the process of jumpstarting delivery using prostaglandin — has gotten a bad rap. We found little justification for this" in the case of women whose water broke prematurely, said principal investigator Dr. Liran Hiersch, who led the study with Dr. Eran Ashwal, both of TAU's Sackler School of Medicine and the Helen Schneider Hospital for Women at Rabin Medical Center. "People have an idea that everything natural is better, including childbirth. But induction is not necessarily more dangerous for mother and child than Mother Nature herself."
The study was published on August 8, 2016, in the Archives of Gynaecology and Obstetrics.
Fears about induced labor are unjustified
Most expectant mothers are warned about artificially induced deliveries. These warnings counsel that induction may cause a low fetal heart rate, an increased risk of infection to mother and baby, and uterine rupture or excessive bleeding after delivery. "We have found that induction produces healthy mothers and infants, with risk factors similar to those of spontaneous deliveries," Dr. Hiersch said.
The researchers evaluated the perinatal outcome of 625 women admitted to Rabin Medical Center in Israel with prolonged (24-hour) premature rupture of membranes or water breakage. Women who did not exhibit the spontaneous onset of labor within 24 hours from the moment their water broke underwent prostaglandin induction. These were then compared to those women who did develop the spontaneous onset of labor within 24 hours of being admitted. No significant difference was found between the groups regarding maternal age, parity and obstetrical complications.
Women in the induction group were found to be at an increased risk for Caesarean section (CS), but researchers believe this was due mainly to blocked birth canals and not the induction itself.
Artificial induction is a possibility for all expectant mothers who have approached two weeks past their delivery date, who experience high blood pressure or diabetes, who have a uterine infection or who simply haven't experienced contractions despite their water having broken. These women are often hospitalized for 24 hours. But after 24 hours have passed without natural delivery, most medical professionals will induce labor artificially to reduce subsequent risks to mother and child.
Patients should be reassured
"There is a palpable fear among women who are waiting for the contractions to begin," said Dr. Hiersch. "They fear fetal distress, they fear infection, umbilical cord trouble, but we have found no basis for their fears. These mothers should be assured that induced labor poses no increased risk to the health of their babies and themselves."
"This study gives us, medical professionals, the reassurance we require to continue doing what we do. Hopefully, it will also reassure our patients, which is equally important," Dr. Hiersch concluded.
Dr. Hiersch is currently working on finding variables that predict which women may spontaneously go into labor following the premature rupture of membranes.
Findings may lead to a cure for the deadly disease
In a landmark discovery, researchers at Tel Aviv University have unraveled the metastatic mechanism of melanoma, the most aggressive of all skin cancers.
According to a paper published today in the journal Nature Cell Biology, the scientists discovered that before spreading to other organs, a melanoma tumor sends out tiny vesicles containing molecules of microRNA. These induce morphological changes in the dermis in preparation for receiving and transporting the cancer cells. The researchers also found chemical substances that can stop the process and are therefore promising drug candidates.
"The threat of melanoma is not in the initial tumor that appears on the skin, but rather in its metastasis — in the tumor cells sent off to colonize in vital organs like the brain, lungs, liver and bones," said research leader Dr. Carmit Levy of the Department of Human Molecular Genetics and Biochemistry at TAU's Sackler School of Medicine. "We have discovered how the cancer spreads to distant organs and found ways to stop the process before the metastatic stage."
The TAU group worked in close collaboration with Prof. Jörg D. Hoheisel and Laureen Sander at the German Cancer Research Center (DKFZ) in Heidelberg, Dr. Shoshi Greenberger at the Sheba Medical Center at Tel HaShomer, Israel and Dr. Ronen Brenner at the Wolfson Medical Center in Holon, Israel. Lab research was led by Dr. Shani Dror of Dr. Levy's research group.
Morphological changes in the dermis
Melanoma, the most aggressive and lethal type of skin cancer, causes the death of one person every 52 minutes according to data from the Skin Cancer Foundation, and the number of diagnosed cases has been on the rise for the past three decades. Despite a range of therapies developed over the years, there is still no full remedy for this life-threatening disease. The new study proposes novel and effective methods for diagnosing and preventing this most deadly of skin cancers.
The researchers began by examining pathology samples taken from melanoma patients. "We looked at samples of early melanoma, before the invasive stage," Dr. Levy said. "To our surprise we found changes in the morphology of the dermis — the inner layer of the skin — that had never before been reported. Our next task was to find out what these changes were, and how they related to melanoma."
In the ensuing study, the group was able to discover and block a central mechanism in the metastasis of melanoma.
According to Dr. Levy, scientists have known for years that melanoma forms in the outer layer of the skin, the epidermis. At this early stage, the cancer is unable to send off colonizing cancer cells because it has no access to blood vessels — the highways that carry the cells to other parts of the body. With no blood vessels present in the epidermis, the tumor first needs to contact the abundant blood vessels running through the dermis. But how was the connection made?
"We found that even before the cancer itself invades the dermis, it sends out tiny vesicles containing molecules of microRNA," Dr. Levy said. "These induce the morphological changes in the dermis in preparation for receiving and transporting the cancer cells. It then became clear to us that by blocking the vesicles, we might be able to stop the disease altogether."
Transforming melanoma into a nonthreatening illness
Having discovered the mechanism, the researchers proceeded to look for substances that could intervene and block the process in its earliest stages. They found two such chemicals: one (SB202190) inhibits the delivery of the vesicles from the melanoma tumor to the dermis; and the other (U0126) prevents the morphological changes in the dermis even after the arrival of the vesicles. Both substances were tested successfully in the lab, and may serve as promising candidates for future drugs. In addition, the changes in the dermis, as well as the vesicles themselves, can be used as powerful indicators for early diagnosis of melanoma.
"Our study is an important step on the road to a full remedy for the deadliest skin cancer," said Dr. Levy. "We hope that our findings will help turn melanoma into a nonthreatening, easily curable disease."
Dr. Inna Slutsky receives illustrious award for outstanding research in the field of Alzheimer's disease
Tel Aviv University's Dr. Inna Slutsky won the 2016 MetLife Foundation Promising Investigator Award in Medical Research for Alzheimer's Disease from the American Federation for Aging Research for her exemplary medical research in Alzheimer's disease. The award was presented on July 25, 2016, with the during the Alzheimer's Association International Conference in Toronto.
Dr. Slutsky, the first Israeli scientist to ever receive a MetLife Foundation Award, is a member of TAU's Department of Physiology and Pharmacology, Sackler Faculty of Medicine, and Sagol School of Neuroscience. She has focused her research on the breakdown of communication lines between brain cells in the pathology of Alzheimer's disease.
MetLife Foundation gave four awards this year, distributing a total of $350,000 to Dr. Slutsky; Guojun Bu, PhD, of the Mayo Clinic; Mia Kivipelto, MD, PhD, of Karolinska Institutet, Stockholm and Karolinska University Hospital, Stockholm; and John R. Cirrito, PhD, of Washington University School of Medicine. The awards recognize them as trail-blazing scientists who have made significant contributions to the understanding of Alzheimer's disease.
"Our Advisory Committee were so impressed by the potential impact of Dr. Slutsky and Dr. Cirrito's research that they granted them the Promising Investigator awards this year," said Dennis White, President and Chief Executive Officer, of MetLife Foundation at the awards ceremony.
"These four individuals have performed ground-breaking work, and the awards will help further their pioneering research," said past award recipient Dr. David M. Holtzman of Washington University School of Medicine during the ceremony. "Drs. Bu, Kivipelto, Slutsky, and Cirrito join a roster of past winners whose work has gone onto receive recognition in the field and beyond, including the Nobel Prize, the Potamkin Prize, and TIME Magazine's scientist of the year."
MetLife Foundation has been presenting these prestigious awards to outstanding researchers in the field of Alzheimer's disease for 30 years. Since 1986 it has granted more than $18 million to 88 awardees at 52 institutions in eight countries.
Cognitive functions play an active role in the gait pattern of Parkinson's patients, say TAU researchers
A new study by Tel Aviv University researchers demonstrates that the prefrontal cortex, the part of the brain associated with cognitive functions, plays a major role in "Parkinson's Gait." It suggests a radically new understanding of the mechanism underlying gait difficulties in people with Parkinson's disease (PD) and may lead to new therapeutic approaches.
The study was led by Prof. Jeffery Hausdorff of TAU's Sackler School of Medicine and Dr. Anat Mirelman of the Department of Neurology at TAU's Sackler School of Medicine, co-directors of the Center for the Study of Movement, Cognition and Mobility at the Tel Aviv Medical Center; and conducted in large part by Dr. Inbal Maidan of Tel Aviv Medical Center. The work was recently published in the journals Parkinsonism and Related Disorders and Neurorehabilitation and Neural Repair.
More than motor deficits involved
The ability to walk safely and independently is central to functional independence and quality of life. That ability is impaired in people with PD, rendering the most basic and commonplace tasks nearly impossible.
Researchers had previously theorized that motor deficits associated with PD were the direct cause of impaired walking, the reduced ability to multitask while walking, and the dangerous falls associated with the disease.
However, when TAU researchers asked patients to walk and complete another task — e.g., a verbal fluency task such as naming fruits or simple serial subtractions — at the same time, also called "dual tasking," the gait pattern of patients with PD became worse. They walked slower and with less stability. This suggested that cognitive resources were being used as they walked.
"Work by our group has demonstrated that cognitive control deficits play an active role in the walking difficulties experienced by many people with Parkinson's," said Prof. Hausdorff.
New pictures of the problem
The team used functional near infrared spectroscopy (fNIRS) to show that cognitive resources are utilized by PD patients much more often than by healthy individuals. "The advantage of fNIRS is that we can measure brain activation during actual walking," said Dr. Mirelman. "These results are consistent with our study using MRI that found brain activity in Parkinson's patients was activated in the prefrontal cortex even during 'imagined walking.'
"The overactivation of the prefrontal cortex has a two-pronged effect in Parkinson's patients," Dr. Mirelman continued. "Because the prefrontal cortex is 'saturated,' it is unable to perform other tasks, impairing gait and creating cognitive deficits. The debilitation is two-fold."
Even when patients were lying flat in the MRI and merely imagining themselves walking, there was a "ceiling effect" — they were unable to recruit additional cognitive resources to tackle more difficult tasks involved with walking. "The increased activation during normal walking curtails the ability of Parkinson's patients to recruit further cognitive resources during other challenging tasks," said Prof. Hausdorff. "It may even exacerbate the high risk of falling in these patients."
The team is now conducting research to better understand the underlying mechanisms of the brain activation pattern and therapeutic approaches that may improve gait and reduce the risk of falls. The information is critical to the design of appropriate therapies such as virtual reality or non-invasive brain stimulation to improve neural efficiency.
Researchers at Tel Aviv and Harvard Universities develop method to control collagen-cell proliferation that produces scarring
A group of researchers from Tel Aviv University and Harvard University has devised a new non-invasive method to prevent burn scarring caused by the proliferation of collagen cells. They are using short, pulsed electric fields prevent the formation of burn-related hypertrophic scars — raised tissue caused by excessive amounts of collagen.
Research for the study was led by Dr. Alexander Golberg of TAU's Porter School of Environmental Studies, together with Dr. Martin Yarmush of the Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Burns Hospital in Boston. It was recently published in the Journal of Investigative Dermatology.
Ten percent of all unintentional-injury deaths are the result of fire-related burns, according to the World Health Organization. But even for those who survive the destruction of skin and tissue cells, the road to recovery is never ending. Post-burn scarring creates lifelong physical, psychological and social challenges.
Relieving lifelong suffering
"People don't die from scars, but they do suffer from them," said Dr. Golberg. "We believe that the technology we developed, called partial irreversible electroporation (pIRE), can be used to prevent debilitating burn scars from forming."
The non-invasive pIRE technique harnesses microsecond-pulsed, high-voltage, non-thermal electric fields to control the body's natural response to trauma — the proliferation of collagen cells that cause permanent scarring at the site of injury. The technique partially destroys cells in the wound with short, pulsed electric fields that cause irreversible damage to the collagen cells. But the researchers had to find a delicate balance so that the technique didn't create a new wound or "overheal" the existing wound, because scarring is the body's natural way of healing.
The researchers treated burn injuries in rats in five therapy sessions over six months, then assessed them using an imaging technique developed by Drs. Martin Villiger and Brett Bouma's group at the Wellman Center of Photomedicine at Massachusetts General. The researchers found a 57.9% reduction of the scar area in comparison with untreated scars.
Next step: Human clinical studies
"Surgical excision, laser therapy, electron-beam irradiation, mechanical compression dressing, silicone sheet application and other techniques have been tested to treat scars over the years," said Dr. Golberg, "but there have been only modest improvements in the healing outcomes among all these treatments.
"Scarring is a very complex process, involving inflammation and metabolism," said Dr. Golberg. "We have found a way to partially prevent scar formation in animal models. Next we need to raise funding to develop a device for the clinical study on humans."
The study was supported by the Shriners Foundation, which funds research on pediatric burns.
Study pinpoints when melanoma cells metastasize to the brain months before they develop into fatal tumors
When malignant melanoma metastasizes to the brain, it is a death sentence for most patients. Metastatic melanoma is the deadliest of the skin cancers and the mechanisms that govern early metastatic growth and interactions of metastatic cells with the brain microenvironment remain shrouded in mystery.
A new Tel Aviv University study reveals a novel way of detecting brain micrometastases months before they transform into malignant inoperable growths. According to the research, micro-tumor cells hijack astrogliosis, the brain's natural response to damage or injury, to support metastatic growth. This knowledge may lead to the detection of brain cancer in its first stages and permit early intervention.
The study was led by Dr. Neta Erez of the Department of Pathology at TAU's Sackler Faculty of Medicine and published in Cancer Research.
Following the path to cancer
Dr. Erez and her team used mouse models to study and follow the spontaneous metastasis of melanoma in the brain. She and her partners recapitulated all the stages of metastasis: the initial discovery of melanoma in the skin, the removal of the primary tumor, the micrometastatic dissemination of cancer cells across the body, the discovery of a tumor and death.
The detection of metastasis depends on imaging techniques that still can't detect micrometastases. Melanoma patients whose initial melanoma was excised believe that everything is fine for months or years following the initial procedure.
But following the removal of the primary tumor, micrometastatic cells learn to communicate with cells in their new microenvironment in the brain — cells which are, at first, hostile to them. But eventually a tumor appears. These cells travelled across the body to the brain or other organs but were undetectable at the micro level. When they become detectable, it is too late for treatment.
Opening the "black box"
Dr. Erez calls the period of the initial growth of disseminated micrometastatic cells in distant organs the metastasis' "black box" — the history of melanoma in the brain. "We believe that we have found the tools to characterize this black box," said Dr. Erez. "And this is key to developing therapeutic approaches that may prevent brain metastatic relapse.
"Every organ in body has a defense system that detects intruders," said Dr. Erez. "Much of this is regulated by support cells in the brain. When there is tissue damage due to a stroke or viral infection, these cells are activated and induce an inflammatory response.
"At the earliest stages of metastasis, we already see astrogliosis and inflammation. The brain perceives the micrometastatic invasion as tissue damage, activating inflammation — its natural defense mechanism. We found that the inflammation unfortunately gets hijacked by tumor cells that are able to grow faster and penetrate deeper because the blood vessels in the brain are more permeable than in any other part of the body. We found that all of this happens very early on."
Dr. Erez is currently studying detailed molecular pathways in the brain's biological response to find a way to block the metastases. "We're hoping to develop the detection tools for humans that we developed in mice," said Dr. Erez. "We're also trying to find molecular targets that will allow us to prevent metastasis rather than trying to treat it."
TAU researchers discover the on/off button for inheriting responses to environmental changes
According to epigenetics — the study of inheritable changes in gene expression not directly coded in our DNA — our life experiences may be passed on to our children and our children's children. Studies on survivors of traumatic events have suggested that exposure to stress may indeed have lasting effects on subsequent generations. But how exactly are these genetic "memories" passed on?
A new Tel Aviv University study pinpoints the precise mechanism that turns the inheritance of environmental influences "on" and "off." The research, published last week in Cell and led by Dr. Oded Rechavi and his group from TAU's Faculty of Life Sciences and Sagol School of Neuroscience, reveals the rules that dictate which epigenetic responses will be inherited, and for how long.
"Until now, it has been assumed that a passive dilution or decay governs the inheritance of epigenetic responses," Dr. Rechavi said. "But we showed that there is an active process that regulates epigenetic inheritance down through generations."
Passing stress from one generation to the next
Researchers have been preoccupied with how the effects of stress, trauma, and other environmental exposures are passed from one generation to the next for years. Small RNA molecules — short sequences of RNA that regulate the expression of genes — are among the key factors involved in mediating this kind of inheritance. Dr. Rechavi and his team had previously identified a "small RNA inheritance" mechanism through which RNA molecules produced a response to the needs of specific cells and how they were regulated between generations.
"We previously showed that worms inherited small RNAs following the starvation and viral infections of their parents. These small RNAs helped prepare their offspring for similar hardships," Dr. Rechavi said. "We also identified a mechanism that amplified heritable small RNAs across generations, so the response was not diluted. We found that enzymes called RdRPs are required for re-creating new small RNAs to keep the response going in subsequent generations."
Most inheritable epigenetic responses in C.elegans worms were found to persist for only a few generations. This created the assumption that epigenetic effects simply "petered out" over time, through a process of dilution or decay.
"But this assumption ignored the possibility that this process doesn't simply die out but is regulated instead," said Dr. Rechavi, who in this study treated C.elegans worms with small RNAs that target the GFP (green fluorescent protein), a reporter gene commonly used in experiments. "By following heritable small RNAs that regulated GFP — that 'silenced' its expression — we revealed an active, tuneable inheritance mechanism that can be turned 'on' or 'off.'"
The scientists discovered that specific genes, which they named "MOTEK" (Modified Transgenerational Epigenetic Kinetics), were involved in turning on and off epigenetic transmissions.
"We discovered how to manipulate the transgenerational duration of epigenetic inheritance in worms by switching 'on' and 'off' the small RNAs that worms use to regulate genes," said Dr. Rechavi. "These switches are controlled by a feedback interaction between gene-regulating small RNAs, which are inheritable, and the MOTEK genes that are required to produce and transmit these small RNAs across generations.
"The feedback determines whether epigenetic memory will continue to the progeny or not, and how long each epigenetic response will last."
A comprehensive theory of heredity?
Although their research was conducted on worms, the team believes that understanding the principles that control the inheritance of epigenetic information is crucial for constructing a comprehensive theory of heredity for all organisms, humans included.
"We are now planning to study the MOTEK genes to know exactly how these genes affect the duration of epigenetic effects," said Leah Houri-Zeevi, a PhD student in Dr. Rechavi's lab and first author of the paper. "Moreover, we are planning to examine whether similar mechanisms exist in humans."