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Tag: Medicine

New system for detecting Parkinson’s early

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New method tracks early stages of protein aggregation involved in Parkinson’s

Parkinson’s disease is a debilitating neurodegenerative disease, affecting everything from speech, posture and gait to digestion, sleep, impulse control and cognition. Therapies exist that alleviate some symptoms of the disease, but there is still no cure for Parkinson’s, which affects close to one million Americans and 10 million people worldwide.

A new Tel Aviv University study unveils a novel method for detecting the aggregation of the protein alpha-synuclein, a hallmark of Parkinson’s disease. With this knowledge, caregivers could introduce treatment that has the potential to significantly delay disease progression.

By the time a patient is diagnosed with Parkinson’s disease, 50 percent to 80 percent of the dopaminergic cells in the part of the brain called substania nigra are already dead, possibly due to development of toxicity as result of alpha-synuclein aggregation. “We have developed a new method for tracking early stages of aggregation of alpha-synuclein using super-resolution microscopy and advanced analysis,” says Prof. Uri Ashery, co-author of the study and head of TAU’s Sagol School of Neuroscience and TAU’s George S. Wise Faculty of Life Sciences. The research was published in Acta Neuropathologica on May 31.

“Together with our collaborators at Cambridge University, who developed a special mouse model for Parkinson’s disease, we were able to detect different stages of the aggregation of this protein,” Prof. Ashery explains. “We correlated the aggregation with the deteriorating loss of neuronal activity and deficits in the behavior of the mice.”

A big step towards early detection

“This is extremely important because we can now detect early stages of alpha-synuclein aggregation and monitor the effects of drugs on this aggregation,” says Dr. Dana Bar-On of the Sagol School of Neuroscience, a co-author of the study. “We hope that this research can be implemented for use in the early diagnosis of Parkinson’s in patients. We’re currently working to implement the methods in a minimally invasive manner with Parkinson’s patients.”

The researchers, in collaboration with the Max Planck Institute in Gottingen and Ludwig-Maximilians-Universität München, were able to illustrate the effect of a specific drug, anle138b, on this protein aggregation and correlated these results with the normalization of the Parkinson’s phenotype in the mice, according to Prof. Ashery. “This is a significant step forward in the world of Parkinson’s research,” he says.

The researchers are planning to expand their research to family members of Parkinson’s disease patients. “By detecting aggregates using minimally invasive methods in relatives of Parkinson’s disease patients, we can provide early detection and intervention and the opportunity to track and treat the disease before symptoms are even detected,” Prof. Ashery concludes.

TAU Scientists Print First 3D Heart Using Patient’s Own Cells and Materials

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Engineered heart completely matches the immunological, cellular, biochemical and anatomical properties of the patient

In a major medical breakthrough, Tel Aviv University researchers have “printed” the world’s first 3D vascularised engineered heart using a patient’s own cells and biological materials. Their findings were published on April 15 in a study in Advanced Science.

Until now, scientists in regenerative medicine — a field positioned at the crossroads of biology and technology — have been successful in printing only simple tissues without blood vessels.

“This is the first time anyone anywhere has successfully engineered and printed an entire heart replete with cells, blood vessels, ventricles and chambers,” says Prof. Tal Dvir of TAU’s School of Molecular Cell Biology and Biotechnology, Department of Materials Science and Engineering, Center for Nanoscience and Nanotechnology and Sagol Center for Regenerative Biotechnology, who led the research for the study.

Heart disease is the leading cause of death among both men and women in the United States. Heart transplantation is currently the only treatment available to patients with end-stage heart failure. Given the dire shortage of heart donors, the need to develop new approaches to regenerate the diseased heart is urgent.

“This heart is made from human cells and patient-specific biological materials. In our process these materials serve as the bioinks, substances made of sugars and proteins that can be used for 3D printing of complex tissue models,” Prof. Dvir says. “People have managed to 3D-print the structure of a heart in the past, but not with cells or with blood vessels. Our results demonstrate the potential of our approach for engineering personalized tissue and organ replacement in the future.”

Research for the study was conducted jointly by Prof. Dvir, Dr. Assaf Shapira of TAU’s Faculty of Life Sciences and Nadav Moor, a doctoral student in Prof. Dvir’s lab.

 

​”At this stage, our 3D heart is small, the size of a rabbit’s heart,” explains Prof. Dvir. “But larger human hearts require the same technology.”

The secret to a new heart

For the research, a biopsy of fatty tissue was taken from patients. The cellular and a-cellular materials of the tissue were then separated. While the cells were reprogrammed to become pluripotent stem cells, the extracellular matrix (ECM), a three-dimensional network of extracellular macromolecules such as collagen and glycoproteins, were processed into a personalized hydrogel that served as the printing “ink.”

After being mixed with the hydrogel, the cells were efficiently differentiated to cardiac or endothelial cells to create patient-specific, immune-compatible cardiac patches with blood vessels and, subsequently, an entire heart.

According to Prof. Dvir, the use of “native” patient-specific materials is crucial to successfully engineering tissues and organs.

“The biocompatibility of engineered materials is crucial to eliminating the risk of implant rejection, which jeopardizes the success of such treatments,” Prof. Dvir says. “Ideally, the biomaterial should possess the same biochemical, mechanical and topographical properties of the patient’s own tissues. Here, we can report a simple approach to 3D-printed thick, vascularized and perfusable cardiac tissues that completely match the immunological, cellular, biochemical and anatomical properties of the patient.”

What organ would you like?

The researchers are now planning on culturing the printed hearts in the lab and “teaching them to behave” like hearts, Prof. Dvir says. They then plan to transplant the 3D-printed heart in animal models.

“We need to develop the printed heart further,” he concludes. “The cells need to form a pumping ability; they can currently contract, but we need them to work together. Our hope is that we will succeed and prove our method’s efficacy and usefulness.

 

“Maybe, in ten years, there will be organ printers in the finest hospitals around the world, and these procedures will be conducted routinely.”

New genetically encoded sensor isolates hidden Leukemic cells

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Cells express surface markers that help them escape most targeted therapies, Tel Aviv University researchers say

Understanding how leukemic stem cells are regulated has become an important area of cancer research. All stem cells can multiply, proliferate and differentiate. Because of these qualities, leukemic stem cells are the most malignant of all leukemic cells. 

A team of Tel Aviv University researchers have now devised a novel biosensor that can isolate and target leukemic stem cells. The research team, led by Dr. Michael Milyavsky of the Department of Pathology at TAU’s Sackler School of Medicine, discuss their unique genetically encoded sensor and its ability to identify, isolate and characterize leukemic stem cells in a study published on January 31 in Leukemia.

Raising the survival rate for blood cancers

“The major reason for the dismal survival rate in blood cancers is the inherent resistance of leukemic stem cells to therapy,” Dr. Milyavsky says. “But only a minor fraction of leukemic cells have high regenerative potential, and it is this regeneration that results in disease relapse. A lack of tools to specifically isolate leukemic stem cells has precluded the comprehensive study and specific targeting of these stem cells until now.”

Until recently, cancer researchers used markers on the surface of the cell to distinguish leukemic stem cells from the bulk of cancer cells, with only limited success. “There are hidden cancer stem cells that express differentiated surface markers despite their stem cell function. This permits those cells to escape targeted therapies,” Dr. Milyavsky explains. “By labeling leukemia cells on the basis of their stem character alone, our sensor manages to overcome surface marker-based issues.

“We believe that our biosensor can provide a prototype for precision oncology efforts to target patient-specific leukemic stem cells to fight this deadly disease.”

Personalized medical testing

The scientists searched genomic databases for “enhancers,” the specific regulatory regions of the genome that are particularly active in stem cells. Then they harnessed genome engineering to develop a sensor composed of a stem cell active enhancer fused with a fluorescence gene that labels the cells in which the enhancer is active.

The scientists were also able to demonstrate that sensor-positive leukemia stem cells are sensitive to a known and inexpensive cancer drug called 4-HPR (fenretinide), providing a novel biomarker for patients who can potentially benefit from this drug.

“Using this sensor, we can perform personalized medicine oriented to drug screens by barcoding a patient’s own leukemia cells to find the best combination of drugs that will be able to target both leukemia in bulk as well as leukemia stem cells inside it,” Dr. Milyavsky concludes. “We’re also interested in developing killer genes that will eradicate specific leukemia stem cells in which our sensor is active.”

The researchers are now investigating those genes that are active in leukemic stem cells in the hope finding druggable targets.

New blood test could detect genetic disorders during first trimester

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Test could map the fetal genome and detect innumerable diseases caused by minuscule impairments, Tel Aviv University researchers say

Tel Aviv University researchers have developed a new blood test for genetic disorders that may allow parents to learn about the health of their baby as early as 11 weeks into pregnancy.

The simple blood test lets doctors diagnose genetic disorders in fetuses early in pregnancy by sequencing small amounts of DNA in the mother’s and the father’s blood. A computer algorithm harnessing the results of the sequencing would then produce a “map” of the fetal genome, predicting mutations with 99% or better accuracy depending on the mutation type.

Prof. Noam Shomron of TAU’s Sackler School of Medicine led the research, which was conducted by TAU graduate student Tom Rabinowitz with Avital Polsky, Artem Danilevsky, Guy Shapira and Chen Raff, all from Prof. Shomron’s lab. The study is a collaboration with Dr. David Golan of the Technion-Israel Institute of Technology and Prof. Lina Basel-Salmon and Dr. Reut Tomashov-Matar of Rabin Medical Center. It was published on February 20 in the journal Genome Research.

A safe and simple procedure

“Noninvasive prenatal tests are already available for chromosome disorders such as Down syndrome,” Prof. Shomron says. “Our new procedure is based on fetal DNA fragments that circulate freely in maternal blood and bears only a minimal risk for the mother and fetus compared with such invasive techniques as the amniotic fluid test. We will now be able to identify numerous mutations and diseases in a safe and simple procedure available at the doctor’s office.

“The genetic mechanism behind Down syndrome affects a very large portion of the genome and therefore is easier to detect,” Prof. Shomron explains. “We performed upgraded noninvasive fetal genotyping, using a novel approach and an improved algorithm, to detect many other diseases that are caused by smaller parts of the genome. This is like looking at a map of the world and noticing not only that a continent is missing, but also that a single house is missing.

“The practical applications are endless: a single blood test that would detect a wide range of genetic diseases, such as Tay-Sachs disease, cystic fibrosis and many others.”

An algorithm for DNA

Prof. Shomron and colleagues tested blood samples from three families at Rabin Medical Center in the 11th week of gestation. They extracted maternal and paternal DNA from their white blood cells and fetal DNA from a placental cell sample. They also extracted circulating cell-free fetal DNA from the maternal blood.

“We sequenced all these DNA samples and created a computer algorithm that utilizes the parental DNA as well as the cell-free fetal DNA to reconstruct the fetal genome and predict mutations,” says Prof. Shomron. “We compared our predictions to the true fetal DNA originating from the placenta. Our model is the first to predict small inherited insertions and deletions. The method described can serve as a general framework for noninvasive prenatal diagnoses.”

The researchers are working on further improving the accuracy of the method and extending it to detect even more types of mutations.

 

 

Adolescents with Celiac disease at higher risk of eating disorders

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Teenage girls who are overweight and have Celiac Disease are at highest risk of developing eating disorders

Celiac disease is a chronic condition, characterized by inflammation and atrophy of the small intestine. It affects roughly 1 in 100 people, and a strict, lifelong gluten-free diet is the only remedy. A new Tel Aviv University study finds a link between the disaese and a higher incidence of disordered eating behavior during adolescence and young adulthood.

The researchers found that 19% of female teens and 7% of male teens with CD exhibited eating disorders, compared to 8% and 4% of adolescents who did not have CD. Disordered eating behaviors affect about 10% of adolescents and refer to a wide range of abnormal eating behaviors, including binge eating, dieting, skipping meals regularly, self-induced vomiting and obsessive calorie counting. These behaviors are most common among older, overweight female adolescents with CD.

The study was led by Dr. Itay Tokatly-Latzer of TAU’s Sackler Faculty of Medicine and the Department of Pediatrics at Chaim Sheba Medical Center. It was overseen by Dr. Orit Pinhas-Hamiel and conducted by Dr. Daniel Stein, Dr. Batia Weiss and Prof. Liat Lerner-Geva, all of TAU’s Sackler Faculty of Medicine. The results were published in Eating and Weight Disorders.

Early warning signs are crucial

“We discovered an increased occurrence of disordered eating behavior among adolescents with CD,” Dr. Tokatly-Latzer says. “Caregivers of Celiac patients should be aware of the possibility of them having eating disorders. Early recognition of this can prevent the deterioration of these states into full-blown disorders such as anorexia nervosa and bulimia.

“These eating patterns can lead to a failure to meet nutritional and metabolic needs, which cause severe impairment to psychosocial functioning,” Dr. Tokatly-Latzer continues. “Primary care physicians and gastroenterologists who encounter adolescents with CD should increase their awareness to the possibility of this population having disordered eating behavior. Once the suspicion is raised, they can refer them for psychological and nutritional treatment.”

The researchers conducted a web-mediated survey on 136 adolescents aged 12-18 with CD. The survey assessed the participants’ rate of disordered eating behavior as well as their adherence to a gluten-free diet. The survey, conducted over the course of a year, included two self-rating questionnaires: the Eating Attitudes Test-26 and the gluten-free diet questionnaire. Only 32% of the participants reported a strict adherence to a gluten-free diet.

What medical teams should watch for

“Eating disorders have a perplexing etiology that includes biological, sociological, psychological and environmental elements,” Dr. Tokatly-Latzer explains. “Not only does the excessive preoccupation with food increase the likelihood of individuals with Celiac to develop eating disorders, but there is a major aspect that involves food limitation of any kind that probably triggers a predisposition for developing pathological eating tendencies.

“This study should raise awareness for medical teams to the importance of closely monitoring adolescents with CD for disordered eating behavior, especially when they are female, overweight or older. Since individuals with disordered eating behavior are at increased risk of developing a clinical form of an eating disorder, early identification and intervention may improve therapeutic outcomes.”

Conversations in the Clean Room

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At the shared laboratories of the Center for Nanoscience and Nanotechnology, casual conversations between scientists can lead to breakthroughs

A chemist and a physicist walk into a clean room. No, this is not the one about how many people it takes to change a light bulb. Nor is it the one about two Israelis and three opinions. This is a true story about how two doctoral students from different fields got talking and realized that they may be able to use chemistry to solve a nagging problem in physics. “These students were the best kind – curious and open to new ideas and different ways of approaching a problem,” says Prof. Gil Markovich of the Raymond and Beverly Sackler School of Chemistry. Prof. Yoram Dagan, Raymond and Beverly Sackler School of Physics and Astronomy, nods in agreement.

Markovich and Dagan were the students’ respective PhD advisors and quickly saw the benefit of collaborating. In their research, they sought a solution to prevent damage to the surface of semiconductors – small components that control electrical current in devices such as computers and mobile phones, which damage the functioning of the devices.

For this kind of research, a particularly sterile laboratory is required. The special conditions in the “clean room” include a constant temperature of 20 degrees, 50 percent humidity, and a very powerful filter that prevents the entry of dust particles into the laboratory space and is responsible for creating a sterile work environment. These conditions are essential for the production of certain materials, especially electronic chips, which can be disrupted by something as tiny as a grain of dust.

From cell phones to thermal cameras  

The scientists are using a chemical rather than physical process to create an electrical insulating thin film the thickness of a single atom. According to Dagan, “Unlike in physics, where non-organic materials are used, we used organic compounds to get the components that create the atom-thick layer.” In the process carried out by the scientists, they heated organic compounds to the point of dissolution. Once they touch the surface, they receive additional energy and break down until the process stops on its own. “This creates only a single layer of the insulating material, because there is not enough energy to form another layer,” Dagan explains. “In a cheap and rapid chemical process, we were able to offer an alternative to complicated and costly processes, and even to achieve a better result.”

Their invention could improve microelectronics in all the devices we carry in our pockets and have in our homes by making them faster, more efficient and more compact. “This is a long-term project – an idea that may be implementable twenty years down the line. Yet exploring this basic physics problem using nano-chemistry led us to an application that can be realized today,” says Dagan.

Markovich and Dagan have teamed up with industry experts for guidance in applying their technology to improve resolution in infrared cameras used for defense and security installations. The Israel Innovation Authority (formerly the Office of the Chief Scientist) has invested in the project with a grant reserved solely for projects that have a good chance to be commercialized in Israel. “It all begins, though, with basic science. Basic science is the foundation of knowledge. When we discover new possibilities and new materials, applications can grow,” stresses Dagan.

Collaboration opens new possibilities

Markovich and Dagan share a passion for unlocking the secrets of the universe: “We are both interested in origins,” says Dagan. “Gil researches the interaction of minerals with amino acids and DNA – the original building blocks of life.  I am interested in the fundamental properties of matter and materials. I would not think up chemical approaches to physical problems by myself. Our collaboration is opening up new possibilities.” says Dagan.

“This has been a fun ride,” adds Markovich. “First, Yoram is a nice person. And I never worked on these kinds of problems before. We have ideas for cooperation on chemical ways to create new materials for quantum computing. The future is wide open.” 

Featured iage:Prof. Gil Markovich and Prof. Yoram Dagan (Photo: Yoram Reshef)

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