Ultrasound remotely triggers immune cells to attack tumors in mice without toxic side effects
Bioengineers at the University of California San Diego have developed a cancer immunotherapy that pairs ultrasound with cancer-killing immune cells to destroy malignant tumors while sparing normal tissue.
The new experimental therapy significantly slowed down the growth of solid cancerous tumors in mice.
The team, led by the labs of UC San Diego bioengineering professor Peter Yingxiao Wang and bioengineering professor emeritus Shu Chien, detailed their work in a paper published Aug. 12 in Nature Biomedical Engineering.
The work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors.
CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient’s T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.
This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That’s because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells—these effects are known as on-target, off-tumor toxicity.
“CAR T cells are so potent that they may also attack normal tissues that are expressing the target antigens at low levels,” said first author Yiqian (Shirley) Wu, a project scientist in Wang’s lab.
“The problem with standard CAR T cells is that they are always on—they are always expressing the CAR protein, so you cannot control their activation,” explained Wu.
To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on.
“We use ultrasound to successfully control CAR T cells directly in vivo for cancer immunotherapy,” said Wang, who is a faculty member of the Institute of Engineering in Medicine and the Center for Nano-ImmunoEngineering, both at UC San Diego. What’s exciting about the use of ultrasound, noted Wang, is that it can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.
The team’s approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that’s on top of the tumor to activate the CAR T cells. The transducer uses what’s called focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately—in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit)—without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.
The researchers put their CAR T cells to the test against standard CAR T cells. In mice that were treated with the new CAR T cells, only the tumors that were exposed to ultrasound were attacked, while other tissues in the body were left alone. But in mice that were treated with the standard CAR T cells, all tumors and tissue expressing the target antigen were attacked.
“This shows our CAR T-cell therapy is not only effective, but also safer,” said Wu. “It has minimal on-target, off-tumor side effects.”
The work is still in the early stages. The team will be performing more preclinical tests and toxicity studies before it can reach clinical trials.
Lycopene ameliorates diabetic osteoporosis via anti-inflammatory, antioxidation
Shaanxi University of Technology (China), August 10, 2021
According to news originating from Shaanxi University of Technology research stated, “Diabetic osteoporosis (DOP) is one of the complications of diabetes, with high morbidity, and high disability rate. Here, we established a diabetic rat model and administered lycopene to observe its effect on DOP.”
Our news editors obtained a quote from the research from Shaanxi University of Technology: “Our results showed that ten weeks lycopene treatment lowered blood glucose, improved diabetic induced polydipsia, overeating and body weight loss. Lycopene treatment also enhanced bone mineral density, restored bone mechanical and bone Micro-CT parameters of diabetic rats. Subsequently, lycopene decreased serum inflammatory cytokines levels and increased serum anti-oxidant indicators levels. Moreover, lycopene reduced the number of bone marrow adipocytes, and osteoclasts numbers of diabetic rats. The serum bone turnover markers levels were down-regulated after lycopene treatment. Meanwhile, the bone and serum OPG, RUNX 2 expression levels were up-regulated by lycopene in diabetic rats, and the OPG/RANKL ratio was also up-regulated.”
According to the news editors, the research concluded: “This study showed that lycopene could ameliorate diabetic induced bone loss via anti-inflammatory, anti-oxidation, and increasing OPG/RANKL ratio in diabetic rats. Lycopene could be used for nutritional intervention in patients with diabetic osteoporosis.”
Research shows just 8 weeks of meditation studies can make your brain quicker
Birmingham University (UK), August 12, 2021
Researchers at Binghamton University scanned students' brains before and after eight weeks of meditation training. Credit: Binghamton University
Millions of people around the world seek mental clarity through meditation, most of them following or inspired by the centuries-old practices of Buddhism.
Anecdotally, those who meditate say it helps to calm their minds, recenter their thoughts and cut through the "noise" to show what really matters. Scientifically, though, showing the effects of meditation on the human brainhave proved to be tricky.
A new study from Binghamton University's Thomas J. Watson College of Engineering and Applied Science tracked how practicing meditation for just a couple of months changed the brain patterns of 10 students in the University's Scholars Program.
The seed for the research came from a casual chat between Assistant Professor Weiying Dai and lecturer George Weinschenk, MA '01, Ph.D. '07, both from the Department of Computer Science.
Weinschenk is a longtime meditation practitioner whose wife worked as an administrator at the Namgyal Monastery in Ithaca, which is the North American seat of the Dalai Lama's personal monastery.
"I developed very close friendships with several of the monks," he said. "We would hang out together, and I even received instruction from some of the Dalai Lama's teachers. I took classes there, I read a lot and I earned a three-year certificate in Buddhist studies."
Dai has studied brain mapping and biomedical image processing, and while earning her Ph.D. at the University of Pittsburgh, she tracked Alzheimer's disease patients using magnetic resonance imaging (MRI) scans.
"I'm interested in brain research to see how our brains are really functioning and how all different kinds of disease affect our brain," she said. "I really have zero medical training, but I pick up all this knowledge or background from reading the literature and talking with the experts."
The two faculty members had neighboring offices and shared a conversation one day about their backgrounds. Weinschenk mentioned that he had been asked to teach a semester-long class for the Scholars Program on meditation.
"I told Weiying, 'Yeah, meditation really can have a transformative effect on the brain,'" Weinschenk said. "She was a little skeptical, especially about whether such a short amount of time spent learning how to meditate, whether that would make any difference. She suggested we might be able to quantify such a thing with modern technology."
For the fall 2017 semester, Dai secured grant funding, and their collaboration began. Near the beginning of the semester, she took the participants to Cornell University for MRI scans of their brains. Weinschenk taught students how to meditate, told them to practice five times a week for 10 or 15 minutes, and asked them to keep a journal record of their practice. (The syllabus also included other lessons about the cultural transmissions of meditation and its applications for wellness.)
"Binghamton University Scholars are high achievers who want to do the things they are assigned and do well on them, so they didn't require much prompting to maintain a regular meditation routine," he said. "To guarantee objective reporting, they would relate their experiences directly to Weiying about how frequently they practiced."
The results, recently published in the journal Scientific Reports, show that meditation training led to faster switching between the brain's two general states of consciousness.
One is called the default mode network, which is active when the brain is at wakeful rest and not focused on the outside world, such as during daydreaming and mind-wandering. The other is the dorsal attention network, which engages for attention-demanding tasks.
The findings of the study demonstrate that meditation can enhance the brain connection among and within these two brain networks, indicating the effect of meditation on fast switching between the mind wandering and focusing its attention as well as maintaining attention once in the attentive state.
"Tibetans have a term for that ease of switching between states—they call it mental pliancy, an ability that allows you to shape and mold your mind," Weinschenk said. "They also consider the goal of concentration one of the fundamental principles of self-growth."
Dai and Weinschenk are still parsing through the data taken from the 2017 MRI scans, so they have yet to test other Scholars Program students. Because Alzheimer's disease and autism could be caused by problems with the dorsal attention network, Dai is making plans for future research that could use meditation to mitigate those problems.
"I'm thinking about an elderly study, because this population was young students," she said. "I want to get a healthy elderly group, and then another group with early Alzheimer's disease or mild cognitive impairment. I want to see whether the changes in the brain from meditation can enhance cognitive performance. I'm writing the proposal and trying to attract the funds in that direction."
Though once skeptical about the subject, "I'm pretty convinced about the scientific basis of meditation after doing this study," she added. "Maybe I'll just go to George's class when he teaches it so that I can benefit, too!"
Study shows how food preservatives may disrupt human hormones and promote obesity
Cedars-Sinai Medicine Institute, August 9, 2021
Can chemicals that are added to breakfast cereals and other everyday products make you obese? Growing evidence from animal experiments suggests the answer may be "yes." But confirming these findings in humans has faced formidable obstacles - until now.
A study published in Nature Communications details how Cedars-Sinai investigators developed a novel platform and protocol for testing the effects of chemicals known as endocrine disruptors on humans.
The three chemicals tested in this study are abundant in modern life. Butylhydroxytoluene (BHT) is an antioxidant commonly added to breakfast cereals and other foods to protect nutrients and keep fats from turning rancid; perfluorooctanoic acid (PFOA) is a polymer found in some cookware, carpeting and other products; and tributyltin (TBT) is a compound in paints that can make its way into water and accumulate in seafood.
The investigators used hormone-producing tissues grown from human stem cells to demonstrate how chronic exposure to these chemicals can interfere with signals sent from the digestive system to the brain that let people know when they are "full" during meals. When this signaling system breaks down, people often may continue eating, causing them to gain weight.
"We discovered that each of these chemicals damaged hormones that communicate between the gut and the brain," said Dhruv Sareen, PhD, assistant professor of Biomedical Sciences and director of the Induced Pluripotent Stem Cell Core Facility at the Cedars-Sinai Board of Governors Regenerative Medicine Institute. "When we tested the three together, the combined stress was more robust."
Of the three chemicals tested, BHT produced some of the strongest detrimental effects, Sareen said.
While other scientists have shown these compounds can disrupt hormone systems in laboratory animals, the new study is the first to use human pluripotent stem cells and tissues to document how the compounds may disrupt hormones that are critical to gut-to-brain signaling and preventing obesity in people, Sareen said.
"This is a landmark study that substantially improves our understanding of how endocrine disruptors may damage human hormonal systems and contribute to the obesity epidemic in the U.S.," said Clive Svendsen, PhD, director of the institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine. More than one-third of U.S. adults are considered to be obese, according to federal statistics.
The new testing system developed for the study has the potential to provide a much-needed, safe and cost-effective method that can be used to evaluate the health effects of thousands of existing and new chemicals in the environment, the investigators say.
For their experiments, Sareen and his team first obtained blood samples from adults, and then, by introducing reprogramming genes, converted the cells into induced pluripotent stem cells. Then, using these stem cells, the investigators grew human epithelium tissue, which lines the gut, and neuronal tissues of the brain's hypothalamus region, which regulates appetite and metabolism.
The investigators then exposed the tissues to BHT, PFOA and TBT, one by one and also in combination, and observed what happened inside the cells. They found that the chemicals disrupted networks that prepare signaling hormones to maintain their structure and be transported out of the cells, thus making them ineffective. The chemicals also damaged mitochondria - cellular structures that convert food and oxygen into energy and drive the body's metabolism.
Because the chemical damage occurred in early-stage "young" cells, the findings suggest that a defective hormone system potentially could impact a pregnant mother as well as her fetus in the womb, Sareen said. While other scientists have found, in animal studies, that effects of endocrine disruptors can be passed down to future generations, this process has not been proved to occur in humans, he explained.
More than 80,000 chemicals are registered for use in the U.S. in everyday items such as foods, personal care products, household cleaners and lawn-care products, according to the National Toxicology Program of the U.S. Department of Health and Human Services. While the program states on its website that relatively few chemicals are thought to pose a significant risk to human health, it also states: "We do not know the effects of many of these chemicals on our health."
Cost and ethical issues, including the health risk of exposing human subjects to possibly harmful substances, are among the barriers to testing the safety of many chemicals. As a result, numerous widely used compounds remain unevaluated in humans for their health effects, especially to the hormone system.
"By testing these chemicals on actual human tissues in the lab, we potentially could make these evaluations easier to conduct and more cost-effective," Sareen said.
Social activities help dementia patients stay sharp, avoid depression
University of Sheffield (UK), August 12, 2021
Approximately 6 million people in the U.S. are suffering from dementia, as well 50 million people worldwide. There is currently no cure for the degenerative condition and medical treatments often have side effects such as vomiting, loss of appetite, and muscle pains. Now, researchers say patients can greatly benefit from a type of treatment that doesn’t come with such downsides and helps their brain avoid additional decline.
A new study suggests that mixing with other people helps dementia patients stay sharp and fend off depression. Scientists say the type of treatment known as “cognitive stimulation” could make living with dementia easier for hundreds of thousands of people.
“Dementia is one of the biggest global challenges that we face,” says senior author Dr. Claudia von Bastian, of the University of Sheffield, in a statement. “Our research highlights that cognitive stimulation can be a safe, relatively cheap, and accessible treatment to help reduce some of the core symptoms of dementia and may even alleviate symptoms of depression.”
The researchers analyzed the use of cognitive stimulation as an effective treatment for people with dementia. They found that getting patients involved in social and group activities helped combat depression and boost global cognition.
Global cognition refers to five types of brain function: attention, memory, verbal fluency, language, and awareness. “It’s great that governments now recognize the importance for people to live well with dementia. We’ve seen far more energy and resources put into developing initiatives to support this, such as cognitive stimulation, which is now used widely across the world,” notes co-author Dr. Ben Hicks, of Brighton and Sussex Medical School.
“We still need to learn more about the key ingredients of cognitive stimulation which lead to these benefits and how they influence the progression of dementia. However, the absence of negative side-effects and the low costs of this treatment means the benefits are clear,” adds Dr. von Bastian.
More research is needed to determine whether cognitive stimulation and other non-pharmaceutical treatments could help the growing number of people who suffer fromdementia.
“Our research is the first to comprehensively interrogate the evidence base for its effectiveness, using the most up-to-date statistical techniques. While early signs are positive, there’s an urgent need to improve the rigor of evaluative research and better assess the long-term benefits of cognitive stimulation. People with dementia need effective treatments, and, as a research community, this is what we must deliver,” added Dr. Hicks.
Resveratrol supplementation improves arterial stiffness in type 2 diabetics
Toho University (Japan), August 18 2021
A randomized, double-blind study reported on in the International Heart journal found improvements in arterial stiffness and oxidative stress among type 2 diabetics who were supplemented with resveratrol.
The trial included 50 diabetic men and women who received 100 milligrams resveratrol or a placebo daily for 12 weeks. Cardio-ankle vascular index (CAVI, a novel diagnostic measure of arterial stiffness that is a marker of atherosclerosis) and blood pressure were assessed at the beginning and end of the study, in addition to blood assessments of oxidative stress and other factors.
At the end of the study, subjects who received resveratrol had significantly lower blood pressure, less oxidative stress and decreased arterial stiffness in comparison with values obtained at the beginning of the study. Participants who received a placebo experienced no significant changes in these areas.
“The primary finding in the present study was that oral supplementation of resveratrol for 12 weeks decreased CAVI in patients with type 2 diabetes mellitus,” authors Haruki Imamura, MD, and colleagues at Toho University Sakura Medical Center in Japan write. “Many previous studies have demonstrated increased CAVI in atherosclerotic diseases such as acute coronary syndrome and stroke, and these reports indicate that CAVI reflects organic atherosclerosis.”
They suggest that a reduction in oxidative stress may be one mechanism involved in the improvement in arterial stiffness observed in this study among participants who received resveratrol. Improved endothelial function via increased nitric oxide production may be another mechanism.
