Publisher Health

Iron (Fe) accumulates in the brain cortex with aging. A plethora of studies indicate that progressive iron accumulation in the substantia nigra (SN) in the aged human brain is a major risk factor for Parkinson’s disease (PD) and other neurodegenerative diseases, but not everyone. This is because our body has plans to respond specifically to iron overloading.
A recent study, jointly led by Professor Taejoon Kwon and Professor Hyung Joon Cho in the Department of Biomedical Engineering at UNIST details the neuronal response to excessive iron accumulation, which is associated with age-related neurodegenerative diseases.
By investigating the response of neurons in the SN against age-related iron accumulation, the research team identified a transcriptome profile of aging-related iron accumulation using rats of different ages and confirmed their iron accumulation using the magnetic resonance images. With the additional animal experiments and cell line experiments, they found that two genes (CLU and HERPUD1) responded to age-related iron accumulation, and the knockdown of these genes severely impaired the cellular tolerance for iron toxicity.
“We conjecture that the understanding of the gene expression landscape during age-related iron accumulation can help us to elucidate molecular pathways and putative preventative strategies against neurodegenerative diseases,” noted the research team.
Their findings have been published in the September 2022 issue of Aging Cell, an open-access journal published by John Wiley & Sons. This study has been supported by the Global Ph.D. Fellowship and the University Key Research Institute (UKRI) programs through the National Research Foundation of Korea (NRF). It has also been supported through the grants by the Korea Health Industry Development Institute (KHIDI) and UNIST.
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Materials provided by Ulsan National Institute of Science and Technology(UNIST). Original written by JooHyeon Heo. Note: Content may be edited for style and length.

The cancer therapy known as CAR-T has revolutionized treatment of some blood cancers since it was introduced in 2017. The therapy uses genetically altered immune cells to home in on cancer cells and destroy them.
Now, studying mice with an autoimmune disease similar to multiple sclerosis (MS), researchers at Washington University School of Medicine in St. Louis have shown that the same approach can be used to eliminate unwanted cells that cause autoimmunity. The findings, available online in Science Immunology, extend the powerful tool of immunotherapy to a class of diseases that are often debilitating and difficult to treat.
“We were able to use CAR-T cells to eliminate just the immune cells that are causing the autoimmunity and not other immune cells you might need to protect against viruses or other infection,” said co-senior author Chyi-Song Hsieh, MD, PhD, the Alan A. and Edith L. Wolff Professor of Rheumatology and a professor of medicine and of pathology & immunology. “Our CAR-T cells were very effective at treating mice that have an MS-like disease.”
At the heart of CAR-T therapy are the immune system’s T cells, crucial elements of the body’s defense force. T cells respond to threats such as bacteria, viruses and cancerous cells by coordinating an immune assault and killing foreign organisms and infected or cancerous cells.
But every once in a while, T cells mistake healthy cells for infected cells and turn their weapons on the body’s own cells and tissues, triggering an autoimmune disease. MS is marked by rogue T cells that trigger the destruction of myelin, the protective covering over nerves. As myelin is eaten away, communication between the brain and spinal cord and the rest of the body becomes unreliable, and people begin experiencing symptoms such as fatigue, pain, tingling, vision problems and loss of coordination. Immunosuppressive drugs can quash the self-destructive activity of rogue T cells, but such drugs also suppress helpful T cells and put people at risk of severe infections.
In CAR-T cancer therapies, doctors take a patient’s own T cells, modify them to recognize and vigorously attack his or her specific cancer, and then put them back in the body on a seek-and-destroy mission. Inspired by this approach, the researchers set out to create CAR-T cells equipped to seek out and destroy the rogue T cells that cause MS. The idea was to make CAR-T cells that would function akin to a police department’s internal affairs office, rooting out the bad apples in the T cells defense force while leaving good T cells in place to protect the body.

Biomedical and genetic engineers at Duke University and the Albert Einstein College of Medicine have designed a small fluorescent protein that emits and absorbs light that penetrates deep into biological tissue. Tailored to wavelengths in the near-infrared (NIR) spectrum, this protein can help researchers capture deeper, cleaner, more precise biomedical images.
This work appeared Dec. 1 in the journal Nature Methods.
Imaging deep tissues with light is challenging. Visible light is often quickly absorbed and scattered by structures and molecules in the body, preventing researchers from seeing deeper than a millimeter within a tissue. If they do manage to probe further, substances like collagen or melanin often muddy the image, creating the equivalent of background noise through their natural fluorescence.
“Biological molecules naturally absorb and emit light in the visible spectrum, which is about 350 to 700 nanometers,” said Junjie Yao, assistant professor of biomedical engineering at Duke. “So when using it to image deep tissue, it’s like trying to observe the stars in daylight. The signals get flooded out.”
To wade out from these muddied waters, Yao and his collaborator Vladislav Verkhusha, professor of genetics at Albert Einstein College of Medicine, New York developed a protein that absorbs and emits longer wavelengths of light in the near-infrared (NIR) spectrum.
“Tissue is the most transparent in the 700-1300 nanometer window of NIR light,” said Yao. “At those wavelengths, light can penetrate deeper into a tissue, and because there is less natural background fluorescence to filter out, we can take longer exposures and capture clearer images.”
Verkhusha and his lab used a process called directed molecular evolution to engineer their proteins, using photoreceptors normally found in bacteria as the basis for the structure. These photoreceptors are useful for imaging research because they can switch between a silent and active state when hit with a specific wavelength of light. They can bind with biliverdin, a biomolecule that appears in high quantities in mammalian and human tissues.

A new tool under development by University at Buffalo researchers could one day help clinicians better predict resistance to immunoglobulin therapy among children with Kawasaki disease in the United States.
The new tool — described in a study published earlier this year in the Journal of Pediatric Pharmacology and Therapeutics – lays the groundwork for North America’s first test to predict resistance to therapeutic treatments for the rare disease, but severe inflammatory disease.
Compared to the Kobayashi score — the most widely used method in Japan for predicting resistance to the antibody, intravenous immunoglobulin (IVIG), in Kawasaki disease — the UB-developed tool is twice as accurate for Western New York children, achieving a sensitivity (detection) rate of 54%.
“Neither system is highly sensitive, but the new score may more accurately identify IVIG resistance in Western New York children and other North American populations than the Kobayashi score,” says first author and UB alum Jasdip Singh, PharmD, global scientific communications manager at Eli Lilly and Company.
Kawasaki disease is an acute inflammation of the blood vessels that primarily affects children younger than 5 years of age. The illness is the leading cause of acquired heart disease among children in the U.S., according to the Centers for Disease Control and Prevention. If left untreated, children with the disease can experience life-threatening coronary artery aneurysms.
The standard treatment for Kawasaki disease is IVIG and aspirin. Although most cases are resolved after a single dose of IVIG, 10-20% of children are IVIG resistant and have a higher chance of developing coronary artery aneurysms.

While it has long been recognized that drugs that block the cancer-promoting activity of estrogen reduce risk of developing new breast cancers, a new computer modeling study led by researchers at Georgetown Lombardi Comprehensive Cancer Center and colleagues showed that these treatments could also reduce the risk of dying from the disease in women who are at high risk.
The finding appeared December 1, 2022, in the Journal of Clinical Oncology.
“Recent studies have shown that women diagnosed with estrogen receptor (ER) positive tumors continue to experience breast cancer recurrence and death for as long as 30 years after their primary diagnosis,” says Claudine Issacs, M.D., Leader of the Breast Cancer Program, medical director of the Fisher Center for Hereditary Cancer and Clinical Genomics Research at Georgetown Lombardi and one of the study’s two senior authors.
She says this new evidence prompted researchers to re-examine the lifetime benefits and harms of risk-reducing medications developed for the primary prevention of breast cancer to see if the drugs could, over the long run, reduce the rate of death from the disease.
Based on the available data, recommendations for preventing ER-positive breast cancer with tamoxifen or aromatase inhibitors presumed that women at elevated risk who took the drugs simply reduced their chances of developing the disease, but our modeling study found that, over the long run, there could also be a significant impact on mortality” Isaacs says. “Giving an estrogen blocker to a woman in her 30s who is at high risk could potentially forestall death due to breast cancer for 20 years or more, which would be significant.”
Over the past several decades, a number of large, federally-funded randomized clinical trials have shown that risk-reducing antiestrogen medications such as tamoxifen and aromatase inhibitors could decrease the incidence of ER-positive breast cancer by 30 to 50 percent in women who are at high-risk of developing the disease. Despite evidence from these trials, the drugs have remained underutilized, perhaps due to the risk, albeit low, of endometrial cancer conferred by the drugs as well as other factors.
“What has been missing from our conversation until now is our ability to say to women that these drugs can not only prevent them from getting breast cancer but they can ultimately prevent them from dying of the disease,” Isaacs says.
Studies have shown that chemoprevention drugs are most effective if taken for five years and not longer. This latest study shows that the impact on mortality could confer a long term and persistent benefit for a decade or more.
The study used computer models developed by the Cancer Intervention and Surveillance Modeling Network (CISNET), a National Cancer Institute sponsored consortium, to determine the lifetime benefits and harms of estrogen blockers for women with a five-year risk of developing breast cancer equal to or greater than three percent. The researchers evaluated the effects of estrogen blockers along with annual screening mammograms (and magnetic resonance imaging, or MRI, if necessary) to calculate the risk of invasive breast cancer, breast cancer death, side-effects, false positives and chances of overdiagnosis.
Tamoxifen, and the use of annual mammography (and MRIs, if necessary), reduced the risk of developing new invasive breast cancers by 40% and reduced the risk of breast cancer deaths by 57%. This translates to 95 fewer invasive breast cancers and 42 fewer breast cancer deaths per 1,000 women compared to women who didn’t get a mammogram, an MRI, or risk-reducing drugs. The scientists noted that the drugs were not without downsides, as tamoxifen could increase the number of new endometrial cancers by up to 11 per 1,000 women.
“The Institute of Medicine [now the National Academy of Medicine] suggests that modeling approaches such as ours are going to provide the most definitive answers about the value of these drugs because, given size and cost considerations, a clinical trial would be impractical, even putting aside the fact that evidence of benefit from a clinical trial would take close to 20 years to accrue,” says Isaacs.

A major challenge in testing new therapies for people with intellectual disability is finding accurate tools to measure whether the intervention or medication works. A new study by researchers at the UC Davis MIND Institute and other institutions suggests that the NIH Toolbox Cognition Battery (NIHTB-CB) is a promising option. The study found the test to be sensitive to developmental changes in children, teens and young adults.
“People with lower developmental abilities are often excluded from research studies and clinical trials,” explained David Hessl, professor in the Department of Psychiatry and Behavioral Sciences and corresponding author of the paper. “That means the results of those studies do not apply to everyone, and this entire group is left out from having the potential benefit of a treatment.”
Intellectual disability is characterized by an IQ of about 70 or lower. It affects 1.8 — 3.2% of people worldwide and can occur with conditions such as fragile X syndrome, autism and Down syndrome.
Intellectual disability also presents with adaptive behavior challenges. It affects academic achievement, independence and many aspects of daily life.
What is the NIH Toolbox Cognition Battery?
The NIHTB-CB is a computer or tablet-administered test. It includes a series of brief tasks to assess cognitive functions like attention, working memory and language.

Healthy diets are rich in antioxidants like amino acids, omega-3 fatty acids and vitamin C, but exactly how beneficial these micronutrients are for cardiovascular health has long been controversial. Now a new meta-analysis published in the Journal of the American College of Cardiology provides some clarity.
Researchers systematically reviewed a total of 884 studies available to date on micronutrients taken as dietary supplements and analyzed their data. They identified several micronutrients that do reduce cardiovascular risk — as well as others that offer no benefit or even have a negative effect. More than 883,000 patients were involved in the combined studies.
“For the first time, we developed a comprehensive, evidence-based integrative map to characterize and quantify micronutrient supplements’ potential effects on cardiometabolic outcomes,” said Simin Liu, MD, MS, MPH, ScD, professor of epidemiology and medicine at Brown University and a principal investigator for the study. “Our study highlights the importance of micronutrient diversity and the balance of health benefits and risks.”
The findings could be used as the basis of future clinical trials to study specific combinations of micronutrients and their impact on cardiovascular health, he said.
Antioxidant supplementation has long been thought to play a role in heart health. That’s because these nutrients work to reduce oxidative stress, a known contributor to many cardiovascular diseases. Heart-healthy diets like the Mediterranean diet and the Dietary Approach to Stop Hypertension (DASH) feature foods that are naturally rich in antioxidants. However, results from studies of antioxidant supplements have been inconsistent — one reason why this approach hasn’t yet been widely adopted in preventative cardiology.
“Research on micronutrient supplementation has mainly focused on the health effects of a single or a few vitamins and minerals,” Liu said. “We decided to take a comprehensive and systematic approach to evaluate all the publicly available and accessible studies reporting all micronutrients, including phytochemicals and antioxidant supplements and their effects on cardiovascular risk factors as well as multiple cardiovascular diseases.”
The researchers looked at randomized, controlled intervention trials evaluating 27 different types of antioxidant supplements. They found strong evidence that several offered cardiovascular benefit. These included omega-3 fatty acid, which decreased mortality from cardiovascular disease; folic acid, which lowered stroke risk; and coenzyme Q10, an antioxidant sometimes marketed as CoQ10, which decreased all-cause mortality. Omega-6 fatty acid, L-arginine, L-citrulline, Vitamin D, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein and quercetin also showed evidence of reducing cardiovascular risk.
Not all supplements were beneficial. Vitamin C, Vitamin D, Vitamin E and selenium showed no effect on long-term cardiovascular disease outcomes or type-2 diabetes risk. And beta carotene supplements increased all-cause mortality.
According to the researchers, the findings point to the need for more personalized, precision-based dietary interventions that involve specific combinations of beneficial supplements. Further study is needed, including large, high-quality interventional trials to investigate the long-term effects of certain micronutrients on health.
“Identifying the optimal mixture of micronutrients is important, as not all are beneficial, and some may even have harmful effects,” Liu said.
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Materials provided by American College of Cardiology. Note: Content may be edited for style and length.

Preliminary results offer hope that gene therapy can protect some people with the brain disease driven by a particular gene variant.In a bold attempt to stop the progress of some cases of Alzheimer’s disease, a group of researchers is trying something new — injecting a protective gene into patients’ brains.The trial involved just five patients with a particular genetic risk for Alzheimer’s. They received a very low dose of the gene therapy — a test of safety, which the treatment passed. But the preliminary results, announced Friday during the Clinical Trials on Alzheimer’s Disease conference, showed that proteins from the added gene appeared in the patients’ spinal fluid, and levels in the brain of two markers of Alzheimer’s disease, tau and amyloid, fell. Those findings were promising enough to advance the clinical trial into its next phase.Treatment of another five patients at a higher dose is underway, and the work, initially funded by the nonprofit Alzheimer’s Drug Discovery Foundation, is supported by Lexeo Therapeutics, a fledgling company founded by Dr. Ronald Crystal, who is also chairman of the department of genetic medicine at Weill Cornell Medicine in New York. The hope is to get a stronger response, eventually leading to a treatment that might slow the disease in whom it has started or, even better, protect people at high risk who have no symptoms.Experts not involved in the trial are fascinated.“It’s a very provocative, very intriguing approach,” said Dr. Eliezer Masliah, director of the neuroscience division at the National Institute on Aging.Participants in the study are among the approximately 2 percent of people who have inherited a pair of copies of a gene, APOE4, which markedly increases their risk of Alzheimer’s. For the study subjects, the first symptoms of Alzheimer’s had already emerged — their genetic risk had played out, and they had few options. There is no treatment that is directed specifically at APOE4-driven Alzheimer’s, nor is one on the near horizon.“We’ve known about this risk factor for almost 30 years now,” said Dr. Howard Fillit, co-founder and chief scientific officer at the Alzheimer’s Drug Discovery Foundation. His foundation and other funders have supported efforts to fix the effects of APOE4 or to treat it with drugs, but to no avail.With genetic tests like 23andMe readily available, more and more people are learning that they have two copies of APOE4. For some, like Chris Hemsworth, the 39-year-old star of “Thor,”, the knowledge is life-changing. In an unlikely coincidence, he got the genetic test as part of a documentary show he was making about life extension. When he learned the result, he decided to take a break from acting.An x-ray showing a needle, left, entering the muscles of the neck administering the gene therapy-carrying virus to the spinal fluid.Weill Cornell MedicineIt is not clear exactly how APOE4 makes Alzheimer’s more likely or why some people with two copies of the variant never get the disease.What is known is that APOE4 is one of three gene variants that affect the chances of a person having Alzheimer’s. The others are APOE3 and APOE2. Each person inherits two APOE gene variants, and the combination determines risk.Compared to the most common variant, APOE3, having at least one copy of the APOE4 variant increases risk, and having an APOE2 variant decreases risk.But estimating the lifetime risk conferred by these variants is tricky. The best data, said Dr. Deborah L. Blacker, a geriatric psychiatrist and epidemiologist at Massachusetts General Hospital, indicate that the lifetime risk of Alzheimer’s for those with two APOE4 genes is 30 percent to 55 percent. The lifetime risk in people with one APOE4 gene and one APOE2 gene has not been directly estimated but has appeared to be about 20 percent, Dr. Blacker said.That leads to the idea that if gene therapy floods the brain with APOE2, converting the brain milieu of a person with two APOE4 variants to one that resembles that of a person with one APOE4 and one APOE2, it could possibly slice Alzheimer’s risk in half.Recruitment to try the technique has been slow, said Dr. Sam Gandy, professor of Alzheimer’s disease research at Mount Sinai in New York, who was one of the study investigators. Not everyone wants to sign up to have a virus carrying a gene injected into their brain.But, he said, Alzheimer’s is so dreadful and people with two copies of APOE4 are at such risk that “desperate times call for desperate measures.”The idea for the APOE2 gene therapy emerged 25 years ago, when both gene therapy and the discovery of the APOE variants were in their infancy. Three researchers who were then at Rockefeller University — Dr. Michael G. Kaplitt, now professor of neurological surgery at Weill Cornell Medicine, Dr. Gandy, and Dr. Paul Greengard — published an essay suggesting it.But, Dr. Kaplitt said, the technologies at the time were not sufficient, and the researchers got busy with other projects.The idea, he said, “languished.”Now, with advances that make it feasible, researchers are able to use a harmless virus, A.A.V., to carry copies of the APOE2 gene to the brain. The virus and its gene cargo reach the brain after being injected directly into the spinal fluid.Dr. Kaplitt, who is leading the trial, said that, for ethical reasons, he is not involved with Lexeo.Dr. Robert C. Green, a medical geneticist at Harvard who has studied how people respond to knowing their APOE4 status, cautioned against leaping to conclusions on the basis of so little data from such a tiny study. However, he is not ready to dismiss it out of hand.“It may be a Hail Mary treatment idea for Alzheimer’s disease,” he said. But “as a proof of concept,” he said, “I’m impressed.”

An international team of researchers has uncovered a new mechanism that enables cancer cells to move throughout the body, providing a potential new target to stop metastasis, which is responsible for 90 per cent of cancer deaths.
In findings published in Nature, the team identifies that cancer cells move faster when they are surrounded by thicker fluids, a change that occurs when lymph drainage is compromised by a primary tumour.
“This is really the first time that the viscosity of the extracellular fluid has been looked at in detail,” says John D. Lewis, professor and Bird Dogs Chair in Translational Oncology at the University of Alberta’s Faculty of Medicine & Dentistry. “Now that we know that fluid viscosity signals cancer cells to move in a specific way, we can potentially use drugs to basically short-circuit that signalling pathway and encourage cancer cells to slow down, or even maybe to stop.”
The Lewis lab was invited to join the project led by researchers at Johns Hopkins University, because of its expertise in imaging human cancer cells in real-time motion using the placenta-like chorioallantoic membrane from fertilized chicken eggs.
“I would say we’re the world leaders in this type of imaging,” Lewis says. “Our contribution to the work was to very precisely show that cancer cells change their gene expression when they encounter increased viscosity in the surrounding fluid and become more aggressive. And even when you bring the viscosity back down, these cells stay more aggressive.”
“We then went on to show that when this signalling pathway is perturbed in cancer cells it changes their ability to escape the bloodstream and metastasize,” Lewis says.
This is the third paper the international research team has published. Lewis credits Konstantin Stoletov, senior research associate, for the bulk of his team’s work. He cautions that once a new therapeutic target is identified, it could take 10 to 15 years to develop and test a drug.
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Materials provided by University of Alberta. Original written by Gillian Rutherford. Note: Content may be edited for style and length.

Cambridge scientists have identified an off-patent drug that can be repurposed to prevent COVID-19 — and may be capable of protecting against future variants of the virus — in research involving a unique mix of ‘mini-organs’, donor organs, animal studies and patients.
The research, published today in Nature, showed that an existing drug used to treat a type of liver disease is able to ‘lock’ the doorway by which SARS-CoV-2 enters our cells, a receptor on the cell surface known as ACE2. Because this drug targets the host cells and not the virus, it should protect against future new variants of the virus as well as other coronaviruses that might emerge.
If confirmed in larger clinical trials, this could provide a vital drug for protecting those individuals for whom vaccines are ineffective or inaccessible as well as individuals at increased risk of infection.
Dr Fotios Sampaziotis, from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge and Addenbrooke’s Hospital, led the research in collaboration with Professor Ludovic Vallier from the Berlin Institute of Health at Charité.
Dr Sampaziotis said: “Vaccines protect us by boosting our immune system so that it can recognise the virus and clear it, or at least weaken it. But vaccines don’t work for everyone — for example patients with a weak immune system — and not everyone have access to them. Also, the virus can mutate to new vaccine-resistant variants.
“We’re interested in finding alternative ways to protect us from SARS-CoV-2 infection that are not dependent on the immune system and could complement vaccination. We’ve discovered a way to close the door to the virus, preventing it from getting into our cells in the first place and protecting us from infection.”
From mini-organs and animals…