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A breakthrough medical technology can save the lives of children with heart defects. Scientists have developed the first-ever heart valve that grows with the child, reducing the need for risky heart surgeries in the future.

Children with congenital heart disease who need valve replacement often undergo multiple surgeries because the valve cannot grow as the child's heart grows. They need multiple heart surgeries to change the heart valve to accommodate the growing size of the heart. However, these surgeries are risky and pose a threat to the child's health.

To solve this problem, a team of scientists from Boston Children's Hospital developed a prosthetic valve that mimics the geometry of the human venous valve. Composed of polymeric leaflets attached to a stainless-steel stent, the valve can be expanded by a minimally invasive balloon catheter procedure, reducing invasive open-heart surgeries.

The doctors can use keyhole surgery to insert a rubber tube attached to a deflated balloon in the valve. They can inflate it depending on the child's heart size.

The valve replacement expanding to accommodate different lengths in implanted sheep. This material relates to a paper that appeared in the Feb. 19, 2020, issue of Science Translational Medicine, published by AAAS. The paper, by S.C. Hofferberth at Boston Children's Hospital in Boston, MA; and colleagues was titled, "A geometrically adaptable heart valve replacement." Image Credit: S.C. Hofferberth et al., Science Translational Medicine (2020)

Multiple heart surgeries

Congenital heart valve disease is life-threatening, and children with this condition may need valve replacement early in their lives. However, children grow, and the artificial heart valve may not be able to accommodate the heart's increasing size.

Many children with this condition face high-risk and multiple open-heart surgeries to remove the valves and replace then with bigger ones.

The scientists used computational modeling to predict how their valve replacement expanded to deal with the stress of blood flow. This material relates to a paper that appeared in the Feb. 19, 2020, issue of Science Translational Medicine, published by AAAS. The paper, by S.C. Hofferberth at Boston Children's Hospital in Boston, MA; and colleagues was titled, "A geometrically adaptable heart valve replacement." Credit: S.C. Hofferberth et al., Science Translational Medicine (2020)

For the first time, the new valve, a biomimetic prosthetic valve, adapts to accommodate growth and structural asymmetries within the heart. In previous heart valve models, they contain three leaflet-like flaps providing a one-way inlet or outlet for blood flow. However, in the new heart valve, it only has two flaps, with a geometry designed to maintain closure, and a one-way flow even when the veins expand in diameter.

"Veins carry approximately 70 percent of our blood volume. The vein dimensions can change dramatically depending on body position, yet the valves must remain functional. We mimicked the geometric profile of the human venous valve to design a bi-leaflet valve of programmed dimensions that is adaptable to growth without loss of one-way flow control," Dr.  Sophie C. Hofferberth, a surgical resident at Brigham and Women's Hospital and lead researcher at Boston Children's Hospital, said.

New artificial heart valve on the way

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The new heart valve has been tested in large animal models, computer simulations, and benchtop studies, demonstrating that it works across a broad range of sizes. What is more, it retains functionality and efficacy when it is expanded through a balloon catheter procedure.

The team tested the prosthetic heart valve in growing young lambs. When implanted on the animals, it exhibited good performance without the blockage of blood flow. In another test in other lambs, the valves stayed functional for ten weeks without causing inflammation or injury to the heart tissues.

Though the study requires human testing and longer-follow up times, there is more work needed to validate the design. If it passes through rigorous testing, it can help more than 1.35 million children across the globe who were born with a congenital heart valve disorder.

The researchers also found that the new prosthetic valve promotes favorable blood flow through the valve, reducing the risk for blood clot formation, which is often observed in existing valve replacement devices. With the invasive heart valve device, there are fewer complications that may endanger the life of the child.

The study was published in the journal Science Translational Medicine.

What is congenital heart valve disease?

The heart pumps blood throughout the body throughout the day, and it contains valves that are responsible for keeping the blood from flowing backward. As a result, the blood flow is controlled, and the oxygenated and non-oxygenated blood will not mix.

A congenital heart valve disease happens if one or more of the valves in the heart do not work well, leading to problems such as regurgitation, stenosis, and atresia. Usually, this occurs when a heart's valves do not develop before birth, causing a defect that keeps the valve from closing completely.

Regurgitations happen when the blood backflows because the valve does not close tightly or adequately. The most common cause of blood backflow is a valve prolapse.

Stenosis happens when the flaps become thick, stiff, or fuse, resulting in the inability of the valve to open fully. Stenosis leads to blockage of blood flow. Atresia pertains to a condition when the valve does not have an opening for the blood to pass through.

All these conditions lead to a wide range of heart problems and can endanger the life of the child. Over time, these problems can strain the heart because it works double-time to compensate for the valve defect. It can cause serious problems such as aortic aneurysm, dilated cardiomyopathy, and heart failure.

Source:

National Heart, Lung, and Blood Institute. (2020). Heart Valve Disease. https://www.nhlbi.nih.gov/health-topics/heart-valve-disease.

Journal reference:

Hofferberth, S., Saeed, M., Tomholt, Fernandes, M., Payne, C., Price, K., Marx, G., Esch, J., Brown, J. et al. (2020). A geometrically adaptable heart valve replacement. Science Translational Medicine. https://stm.sciencemag.org/content/12/531/eaay4006?rss=1.

Viruses are parasites. The only way they can grow is by hijacking their hosts. When they infect a human host, viruses use human proteins to multiply and modify the human cells to sustain the infection. At the same time, the human host activates defense mechanisms to fight the infection.

Most current drugs against viral infections target the virus itself. But scientists are interested in developing therapies that aim for host proteins instead, or the genes that produce them, in part because such therapies are believed less likely to elicit drug resistance. A detailed understanding of virus-host interactions is crucial to the success of this strategy.

A team of Gladstone Institutes scientists led by Senior Investigator Nevan Krogan, PhD, has been cataloging host proteins that physically bind to virus proteins. These physical interactions identify human proteins that the virus can use to infect cells and propagate. However, they don't reveal how host proteins work together to facilitate infection.

To address this gap, Krogan and staff scientist David Gordon, PhD, with colleagues at UC San Francisco (UCSF), University College Dublin, and the Mount Sinai School of Medicine, have developed a new way to understand how host cells control HIV infection in human cells.

Their approach entails disrupting host genes rather than proteins. It is based on the idea, pioneered by Krogan, that you obtain richer information about the functions of genes–and the proteins they encode–when you disable the genes in pairs, instead of one by one. In a paper published in Molecular Cell, the team describes a map of the genes controlling HIV infection in human cells, which they built by assessing more than 63,000 combinations of human genes associated with HIV infection.

HIV is a major public health concern, with an estimated 36.7 million people living with chronic infection, and over 20.9 million people receiving continuous treatment. Studying the impact of gene disruptions in pairs rather than one by one yields important information on how genes work together to mediate virus infection, highlighting processes we can target with drugs to inhibit infection."

Nevan Krogan, Ph.D., senior investigator, professor of Cellular and Molecular Pharmacology at UCSF, and the director of the UCSF Quantitative Biosciences Institute

The map, which the team refers to as a viral epistasis map (vE-MAP), is an essential advance for HIV research in several other ways. For one thing, it uncovers a previously unsuspected set of genes required for the growth of the virus in human cells. For another, the vE-MAP can be used to analyze how different HIV mutants affect host cells or to test drugs that disrupt HIV-host interactions.

Strength in numbers

The vE-MAP is an adaptation of the E-MAP, which Krogan and his colleagues pioneered and refined over the past 15 years to identify genes that control how cells grow. At the core of this approach is the Krogan lab's ability to disrupt a large number of genes, test them in pairs, and analyze the results via sophisticated computational methods.

"The principle behind E-MAPs is that when you disrupt two genes at once and examine the impact on a cell, you sometimes see effects that are significantly larger or smaller than you would have predicted from the effect of disrupting either gene alone," said Krogan.

These unexpected effects suggest that the functions of the two genes are related. Moreover, by carrying out these pairwise disruptions across hundreds of genes, scientists can find groups of genes with similar patterns of interactions, a sign that they are likely to take part in the same molecular process.

"And so, instead of finding important genes one at a time, you can all at once identify multiple, distinct networks of genes affecting the process you are studying," said Gordon.

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The E-MAP approach has mostly been used to study cell growth. Gordon, in collaboration with a student from University College Dublin, Ariane Watson, had to modify it to study virus infection. The most tricky part was to implement a sophisticated data acquisition and scoring system, which allowed them to measure HIV infection accurately across hundreds of thousands of samples, and compare the effect of pairwise and single-gene disruptions.

It would be an overwhelming effort to test all combinations of the over 20,000 protein-coding genes in the human genome. Instead, the scientists focused on genes already suspected to influence HIV biology. In particular, they used the genes encoding a large number of human proteins that the Krogan lab had previously found to bind to HIV proteins. In all, they included over 350 genes in their analysis and tested over 63,000 pairwise disruptions.

New players at the HIV-host interface

Although HIV is one of the best-studied human viruses and is now well-controlled by antiretroviral therapy, there is no cure for HIV/AIDS. Moreover, antiretroviral therapy is costly, which can make it impractical in resource-poor countries. The search for new means of halting or eradicating the virus is, therefore, still a priority.

Among the genes that stood out in the vE-MAP were several members of the CNOT family, whose role in HIV biology had never before been established. The authors demonstrated that the CNOT complex promotes HIV infection by suppressing innate immunity in CD4+ T cells, the type of immune cells that HIV preferentially targets in humans. Innate immunity is a defense mechanism by which host cells can fight infection.

"The impact of CNOT on innate immunity is a key, yet previously unrecognized, host pathway critical to HIV infection. It will serve as a potential novel therapeutic target in future studies," said Krogan.

For instance, scientists can now study if targeting the CNOT complex with drugs could be a way to help HIV patients fight the infection more effectively.

Furthermore, the vE-MAP uncovered genes that had little impact when disrupted individually, but a great effect when tested together.

"These genes would be overlooked in classic, single-gene disruption experiments," said Gordon. "They confirm the potential of the vE-MAP to uncover new mechanisms by which HIV interacts with human cells."

Combining drugs that target two of these genes at the same time might thus be a promising therapeutic strategy, especially for a virus such as HIV/AIDS, which has evolved multiple ways of tapping its hosts' resources.

The vE-MAP was also able to pick up genes that specifically interact with a known HIV mutant. This observation bodes well for the ability of the vE-MAP to identify distinct host factors affecting the various forms of HIV, or the virus mutants that arise in response to currently available drugs.

Additional testing with a drug known to interfere with HIV-associated human proteins gives the authors confidence that their vE-MAP approach could, in the future, be used to screen for novel anti-HIV drugs and to understand their mode of action.

"This vE-MAP provides an unprecedented view of how HIV hijacks and rewires the cellular machinery in human cells during infection," said Krogan. "It will generate many new ideas and avenues to identify and test novel therapies."

And the benefits may not be limited to HIV research.

"Our work is proof-of-principle that the vE-MAP approach is a powerful way to map out the interface between HIV and human cells, and to uncover new therapeutic avenues," said Gordon. "We now look forward to testing it on other pathogens."

Source:

Gladstone Institutes

A University of Houston researcher is working to increase health literacy among Hispanics/Latinos (H/Ls) when it comes to Alzheimer's disease (AD). The largest ethnic minority in the U.S., at 18% of the population, H/Ls are 50% more likely to develop Alzheimer's disease than non-Hispanic whites. H/Ls also live longer, develop AD symptoms earlier, are diagnosed at later stages and are less likely to be treated.

Given those statistics, it's startling that Hispanics/Latinos comprise less than 1% of clinical trials for Alzheimer's disease.

"From a social justice perspective, in order to help reduce health disparities we need to involve these communities in the decision-making process," said Luis D. Medina, assistant professor of psychology. He will use a $2.35 million grant from the National Institute on Aging to build his "Engaging Communities of Hispanics for Aging Research Network."

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"There are various barriers to getting involved in research, including health literacy or what people actually know about Alzheimer's disease. In the Hispanic/Latino communities, it is often thought of as just a part of aging," said Medina, who believes the solution begins with education.

The network will launch in two pilot cities, Houston and Denver. Step one is "boot camp translation" wherein community stakeholders are immersed in learning about the disease, and then the tables turn – the community members educate the trainers on how to speak to their communities.

In boot camp translation we break down the medical jargon to consumable, understandable lay language and the community tells us how to do that. The communities have a lot of strengths that we, as researchers, may or may not have. We are hoping to put more seats at the table so that the communities are involved in research infrastructure and help drive research projects."

Luis D. Medina, assistant professor of psychology, University of Houston

Steven Woods, UH professor of psychology and Jennifer Vardeman, UH associate professor of communication, are assisting on the project in collaboration with Baylor College of Medicine, University of Colorado School of Medicine, University of Nevada, Las Vegas and the Lou Ruvo Center for Brain Health at the Cleveland Clinic in Las Vegas.

Medina plans to expand the project to Las Vegas next as he creates a template for other cities to follow.

"This is about lifting all of us up and improving brain health. The more representative our research samples are, the better we can understand the disease," said Medina, who was recently invited to serve on the Alzheimer's Association International Research Grant Program Council to help craft funding opportunity requests for applications, provide expertise during grant review and make funding recommendations. The association is especially interested in Medina's input on issues related to the recruitment of underrepresented populations.

Source:

University of Houston

The 7th annual Metastatic Breast Cancer Research Conference will be hosted by Huntsman Cancer Institute (HCI) at the University of Utah (U of U) in partnership with Baylor College of Medicine and Theresa's Research Foundation on September 10 and 11, 2020. Participants from around the world are invited to discuss metastatic breast cancer including ongoing research and new ideas from early career scientists.

Conference attendees include clinicians, researchers, advocates, and patients who hope to share information and shed light on the need for improved research focus and funding toward metastatic breast cancer, also known as stage IV breast cancer.

The 2020 conference will be held in Salt Lake City under the leadership of Alana Welm, PhD, breast cancer researcher at HCI and professor of oncological sciences at the U of U. "This is one of the most important conferences every year for those of us who focus on metastatic breast cancer research," says Welm. "The unique medley between state-of-the-art clinical and laboratory research, along with incorporation of important patient perspectives, makes it a stimulating and motivating experience for all of us."

The conference will feature sessions on metastatic breast cancer therapy, predictive models, drug development, and more. Invited speakers from around the world will bring their knowledge and expertise to the conference and seek to inspire conversation and collaboration to new approaches to address this challenging disease. Daily keynote address will focus on systemic regulation of metastasis and immunotherapy.

A cure for metastatic breast cancer requires a dedicated, long-term effort to find curative approaches. This conference helps to benchmark these efforts and create the collaborative research environment that is essential for success."  

Matthew Ellis, MB, BCHIR, BSC., PHD, FRCP , professor and director of the Lester and Sue Smith Breast Center at Baylor College of Medicine and Conference Co-Chair

Abstract submissions are encouraged. Limited travel stipends are available for early career investigators who have an abstract accepted. The poster session will be held in partnership with the Metastasis Research Society and GRASP (Guiding Researchers and Advocates to Scientific Partnerships), so that scientists and advocates can view and discuss posters together.

The Metastatic Breast Cancer Research Conference was established as a medical conference in 2014 by Theresa's Research Foundation. Past host institutions include Baylor College of Medicine, Johns Hopkins School of Medicine, the University of Kansas Medical Center, and the Mayo Clinic. The conference received philanthropic support from The Breast Cancer Research Foundation and Huntsman Cancer Foundation.

Source:

Huntsman Cancer Institute

After 50 years of research and the testing of over 1,000 drugs, there is new hope for preserving brain cells for a time after stroke. Treating acute ischemic stroke patients with an experimental neuroprotective drug, combined with a surgical procedure to remove the clot improves outcomes as shown by clinical trial results published today in The Lancet.

The multi-center, double-blinded, randomized trial, led by a team at the Cumming School of Medicine's (CSM) Hotchkiss Brain Institute and Alberta Health Services, investigates the use of the neuroprotective drug nerinetide, developed by NoNO Inc, in two scenarios in the same trial. In one scenario, nerinetide is given to patients in addition to the clot-busting drug alteplase. In the second scenario, patients who were not suitable for alteplase received only nerinetide. Both groups of patients had concurrent endovascular treatment (EVT) to remove the clot.

"Compared to placebo, almost 20 per cent more patients who received nerinetide along with endovascular treatment, but did not receive alteplase, recovered from a devastating stroke – a difference between paralysis and walking out of the hospital," says Dr. Michael Hill, MD, a neurologist at Foothills Medical Centre (FMC) and professor in the departments of Clinical Neurosciences and Radiology at the CSM. "In the patients who received both drugs, the alteplase negated the benefits of the nerinetide."

Hill says the study provides evidence of a biological pathway that protects brain cells from dying when they are deprived of blood flow. Nerinetide targets the final stage of the brain cell's life by stopping the production of nitric oxide within the cell.

"We really believe this is a new scientific observation," says Hill. "There is evidence nerinetide promotes brain cell survival, offering neuroprotection until we can extract the clot. It opens the door to a new way of treating stroke."

Images of patients' brains from the study show the expected size of the damage from the stroke is sizeably reduced when nerinetide is administered and EVT is performed among patients not concurrently receiving alteplase.

After so many studies investigating neuroprotective drugs failed, we are extremely excited by these results. While nerinetide is not approved for use yet, it shows the potential of a new tool to promote recovery from stroke."

Dr. Mayank Goyal, MD, PhD, neuroradiologist at the FMC, and clinical professor in the Department of Radiology at the CSM

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Worldwide, 15 million people suffer a stroke each year – that's one every nine minutes in Canada and every 90 seconds in the United States. The results can be devastating. Ischemic stroke, the most common, is caused by a clot in a blood vessel in the brain. The sudden loss of blood flow causes brain cells to die, which can permanently affect speech, vision, balance and movement.

The international trial enrolled 1,105 patients between March 2017 and August 2019 at centres in North America, Europe, Australia, and Asia – a global academic collaboration bringing together scientists, clinicians, funding agencies, and industry.

"The collaboration between NoNO Inc., the University of Calgary and investigators at 48 leading stroke hospitals around the world has shown how effective such an academic-industry partnership can be in running high-quality, foundational stroke trials that can lead to positive changes in clinical practice," says Dr. Michael Tymianski, MD, PhD, CEO of NoNO Inc. and the inventor of nerinetide.

The results in the current study, called the ESCAPE-NA1 Trial, build on the success of the ESCAPE trial, in which the Calgary Stroke Program proved that a clot retrieval procedure known as EVT can dramatically improve patient outcomes after an acute ischemic stroke. During the procedure, a catheter is inserted in the groin and guided through blood vessels into the brain. A tiny metal mesh device is used to grab the clot and pull it out. The current study investigates whether administering nerinetide in addition to clot retrieval improves the patient's ability to recover.

Source:

University of Calgary

Journal reference:

Hill, M.D, et al. (2020) Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. The Lancet. doi.org/10.1016/S0140-6736(20)30258-0.

Mount Sinai Researchers find social isolation during key developmental windows drives long term changes to activity patterns of neurons involved in initiating social approach in an animal model.

Corresponding Author: Hirofumi Morishita, MDPhD, together with Schahram Akbarian MDPhD Icahn School of Medicine at Mount Sinai, New York, and other coauthors (first author Lucy Bicks).

Bottom Line: Loneliness is increasingly being recognized as a serious threat to mental health and wellbeing in our society. Our study in an animal model shows that social isolation during adolescence leads to long-term disruptions in social behavior and disruptions to activity patterns of a type of inhibitory neuron in the brain, which are frequently disrupted in psychiatric disorders including Schizophrenia. Activity patterns of these inhibitory neurons are sufficient to rescue social deficits induced by juvenile social isolation.

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Results: Social behavior is composed of interactions where mice are actively exploring conspecifics or passively being explored. We find one population of neurons, parvalbumin expressing inhibitory neurons, increases in activity prior to an active, but not a passive social interaction. Brief activity of these neurons is sufficient to promote increased active social behavior. Juvenile social isolation during adolescence disrupts the activity of these neurons, leading to a decoupling of their activity and subsequent active social behavior initiation. Increasing activity of these neurons in adult animals that were socially isolated during adolescence restores normal social behavior.

Why the Research Is Interesting: The findings help us to understand how social experience during key windows of development might shape long term behavioral outcomes through changes to specific circuits in the brain. Understanding how social experience shapes outcomes can help us to overcome social deficits in cases of early life trauma or in neurodevelopmental and psychiatric disorders with social deficits.

Who: Mouse models deprived of social experience during the juvenile period.

When: Mice were deprived of social experience during a juvenile phase and their behavior and physiology were examined in adulthood.

What: The study measured activity of parvalbumin expressing inhibitory neurons during social interaction as well as input drive to these neurons.

How: We measured parvalbumin expressing inhibitory neuron activity during social behavior and manipulated activity of these neurons using advanced technologies.

Study Conclusions: Social experience early in life alters specific patterns of parvalbumin expressing inhibitory neurons in prefrontal cortex. This pattern of activity is essential for active social approach behavior in mice.

Paper Title: Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior.

Source:

The Mount Sinai Hospital / Mount Sinai School of Medicine

Journal reference:

Bicks, L.K., et al. (2020) Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior. Nature Communications. doi.org/10.1038/s41467-020-14740-z.

When you're facing a cancer diagnosis with an average survival span of 12 to 18 months, every milestone is a victory. That makes each wedding invitation, graduation announcement and birthday photo that UCI neuro-oncologist Dr. Daniela Bota receives from her patients a cherished validation of her 12 years of groundbreaking research on glioblastoma multiforme, the most aggressive form of brain cancer. "Because of our work, these people have been able to move on with their lives," she says.

Bota has pushed the boundaries of innovation in her quest to increase the survival rates of individuals with brain tumors, especially glioblastomas. The esteemed physician-scientist has taken a truly comprehensive approach to battling this rare disease, which has a five year survival rate of only 10 percent and claimed the lives of U.S. Sens. Ted Kennedy and John McCain. Bota has conducted clinical trials of multiple cutting-edge treatments that are improving the quantity as well as the quality of life for glioblastoma patients at UCI and beyond.

'So much potential, so much growth'

Bota grew up in Romania, in a family of engineers. It was assumed she'd follow them into the profession – she was a national mathematics champion in her youth – but Bota had another path in mind. "I wanted to make a more significant contribution," she says. "I wanted to combine my analytical side with a place where I could help others. I ended up becoming an M.D.-Ph.D. to blend both."

At USC, Bota earned a doctorate in molecular biology, focusing on neural degeneration. She then went to the University of Kansas for medical school and a residency in neurology. During her shifts, Bota found herself caring for people with brain tumors – and discovered a new direction for her medical career.

The generosity and gratitude of brain tumor patients make it so rewarding to care for them. I see it again and again at UCI. Many of these patients have a terminal diagnosis, but they're volunteering their time and energy to participate in our clinical trials to help us build a better treatment and, hopefully, in the future, a cure."

Dr. Daniela Bota, UCI neuro-oncologist

After a neuro-oncology fellowship at Duke University, Bota joined the faculty of UCI's School of Medicine and the Chao Family Comprehensive Cancer Center in November 2007. "Both my career and UCI in general have grown so tremendously over the dozen years since," says Bota, who's now co-director of the UCI Health Comprehensive Brain Tumor Program. "There has been so much potential, so much growth, so many changes and so much scientific revolution helping us move forward in so many different directions. It's a very exciting time."

A comprehensive approach

The word "comprehensive" carries significant weight in the realm of cancer care centers. The "comprehensive" designation from the National Cancer Institute recognizes an added depth and breadth of research that bridges multiple scientific areas. Just 51 cancer centers in the U.S. carry the designation; the Chao Family Comprehensive Cancer Center is the only one in Orange County. "We offer one of the most innovative and complex portfolios of clinical trials anywhere in the world," Bota says.

Her own multipronged attack against glioblastoma multiforme reflects the center's comprehensive approach. Bota's work on the experimental drug marizomib has generated significant attention and hope. Unlike traditional chemotherapy drugs, marizomib can penetrate the blood-brain barrier – the filtering mechanism that prevents many blood-borne substances from passing into brain tissues – and inhibit cancer growth without causing damage to other parts of the brain.

Over the past 12 years, Bota has shepherded marizomib from preclinical development all the way through a 700-person international phase III clinical trial now underway. "We have a number of patients from our clinical trials who are surviving this tumor for longer periods of time than usually expected," she says.

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Amanda Johnson, a 32-year-old freelance writer in Mission Viejo, has been receiving marizomib for two years under Bota's care. Her large glioblastoma tumor – which straddled both sides of her brain – has shrunk so much that it's no longer measurable. She has returned to work on her novel and even joined a gym. "I feel so happy just to be alive," Johnson says.

Larry Johnson, her father, told Fox News, "I don't think [Amanda] has come to realize how important her survival is to other people and families who are going to find themselves in a similar situation."

Bota strives to reach a point where such cases will be so commonplace that they don't make the news. "That's what success looks like – not having a prominent publication or being part of a game-changing discovery," she says. "It's having patients like Amanda still be here and doing well."

Vaccine trials and right to try

To achieve that goal, Bota tenaciously pursues multiple avenues of treatment. She has been a leader in the use of Optune, a device worn on the head that generates an electrical field that disrupts the growth of cancer cells. "We were among the first in the country to explore and use this technology," Bota says. "Now we're working with physicians from other countries to help them adopt it in their practices."

She is also spearheading two clinical trials on cancer vaccines. "Brain tumors hide behind the blood-brain barrier, so the body doesn't recognize them as not being a normal part of the body," Bota explains. "With our vaccines, we extract cellular markers from the patient's tumor and inject them back into the patient to stimulate the immune system to recognize those tumors, attack them and, if possible, eliminate them."

She adds: "Both studies have been well-received in our neuro-oncological community, which is highly promising. And a significant benefit is that the vaccines function with minimal or no toxicity."

In January 2019, one of Bota's patients who was ineligible for both clinical trials was able to access one of the vaccines through the first successful application of the national Right to Try Act. Passed in May 2018, it allows people with terminal illnesses, in consultation with their doctors, to seek treatment with experimental drugs not yet approved by the Food and Drug Administration directly from pharmaceutical companies. "The law puts patients in charge of their care; they initiate contact with the manufacturer and request therapy," Bota says. "It gives patients who don't qualify for clinical trials another option."

"We offer one of the most innovative and complex portfolios of clinical trials anywhere in the world."

Sharing her expertise

Bota eagerly offers her knowledge beyond the doors of the Chao Family Comprehensive Cancer Center. Whenever she and her husband, Robert, a local psychiatrist, travel back to their home country of Romania, she consults with medical colleagues there, as there are no certified neuro-oncologists in the nation. On days when the couple work on their farm in the Transylvanian Alps, locals come to them – often on foot – for medical advice. The two hope to eventually establish a clinic in the area. "I want to make sure that Romania also benefits from my medical expertise," Bota says.

Back on campus, in her capacity as senior associate dean for clinical research, she uses her vast clinical trial experience to help colleagues in UCI's School of Medicine advance their own research projects into the clinical arena.

"I'm excited by the ability to impact the lives of so many people through this role," Bota says. "Whether it's for burns or vascular disorders or other conditions, people come to UCI for the same reason: We can offer what community hospitals cannot. Being able to make that happen, to create new options for our patients, is what wakes me up in the morning."

Source:

University of California, Irvine

Earlier this year, doctors and researchers celebrated the news that the five-year survival rate for pancreatic cancer had crossed into double digits for the first time -; up from just 6% in 2011.

And while researchers at the University of Michigan Rogel Cancer Center and elsewhere continue to pursue scientific insights into the disease and develop new therapeutic approaches, surgeons on the front line of patient care are also working hard to improve outcomes.

Hari Nathan, M.D., Ph.D., an assistant professor of surgery at Michigan Medicine, sat down with the Michigan Health blog to talk about recent advances in surgical care for patients with pancreatic cancer, and some things patients should look for when evaluating where to seek treatment.

Growing evidence that starting chemo before surgery could improve survival

The best approach for treating pancreatic cancer remains physically removing the cancer through surgery, also called resection, in combination with chemotherapy and sometimes radiation therapy, Nathan says.

"It's been known for decades that adding chemotherapy to resection for pancreas cancer improves survival," he says. "It's a very difficult disease to begin with, and the survival rates are still unacceptably low compared to the progress we have made in a variety of other cancers. But rates are improving -; and part of the reason they're improving is the development of more effective chemotherapy regimens over time."

Recently, surgeons at Michigan Medicine have adopted an emerging practice of administering some or all of a patient's chemotherapy before they undergo an operation.

One recent study, for example, found that patients who underwent chemo before surgery -; known as neoadjuvant chemotherapy -; had a two-year survival rate of 63.7% compared to 53.5% in those who received surgery first.

That difference is driven by multiple reasons. Even in the best hands, these operations are challenging and can be fraught with complications. And we know that when we give chemotherapy after an operation, roughly half of patients aren't healthy enough to complete the intended course."

Hari Nathan, M.D., Ph.D., assistant professor of surgery at Michigan Medicine

Giving chemotherapy on the front end -; before a major operation takes a toll on a patient's body -; increases the likelihood they'll complete more of their chemotherapy, which, in turn, is correlated with better outcomes, he notes.

For some patients, earlier administration of chemotherapy could spare them from going through an operation if there are signs it won't be effective.

"A small percentage of patients will develop additional disease during chemotherapy, or have progression of the tumor," Nathan says. "That's a warning sign that their disease is more aggressive and putting them through a major operation may not be helpful to them."

Helping more patients become candidates for surgery

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In addition to improving the number of patients who complete their course of chemo, the neoadjuvant approach is also expanding the number of patients who are candidates for surgery, Nathan says.

"What we often find with these newer chemotherapy regimens is that they actually can kill parts of the tumor that will make an operation more viable," he says.

In the past, a patient may have been told that their tumor wasn't resectable because it was wrapped around a vital artery.

"But if we can kill off the part of the tumor that was a barrier to a successful surgery, then it makes it possible to go in and do the operation," Nathan says.

"In a lot of ways, what we're doing in pancreatic cancer now mimics what we've been doing in other cancers for a while," he adds. "The difference is that in colorectal cancer, for example, we've had more effective chemotherapy agents, and so we've been willing to be more surgically aggressive. And now with pancreatic cancer, we're finally getting to that point where we have these more effective chemotherapy regimens."

Where patients get care can make a big difference

There are a number of reasons why receiving care at a nationally ranked hospital or academic medical center, like Michigan Medicine, can also make a big difference for patients, Nathan says.

The first is access to new, otherwise unavailable experimental treatments through clinical trials.

For example, Nathan says, U-M is a site for a trial enrolling patients who are not initially eligible for surgery because their pancreatic cancer involves major blood vessels or other tissue in the abdomen. The trial is to test an investigational medicine that helps chemotherapy to better attack the tumor, with a goal, ultimately, of making the patients candidates for surgery.

Second, larger, high-volume, multidisciplinary centers will have more experience in specifically treating pancreatic cancer (Michigan Medicine was recently designated a National Pancreas Foundation Center of Excellence for Pancreatic Cancer, one of just two in the state.)

"I would argue that medical centers like U-M, by virtue of the breadth and depth of the system as a whole, can provide the highest quality care," Nathan says. "In addition to the quality of our surgeons, our medical oncologists, radiation oncologists, radiologists, geneticists and nutritionists all have expertise in pancreatic cancer. Everybody in our multidisciplinary pancreatic clinic has a large focus of their practice devoted to taking care of patients with pancreas cancer. That's not the case everywhere."

Source:

Michigan Medicine – University of Michigan

The addition of dietary L-serine, a naturally occurring amino acid necessary for formation of proteins and nerve cells, delayed signs of amyotrophic lateral sclerosis (ALS) in an animal study.

The research also represents a significant advance in animal modeling of ALS, a debilitating neurodegenerative disease, said David A. Davis, Ph.D., lead author and research assistant professor of neurology and associate director of the Brain Endowment Bank at the University of Miami Miller School of Medicine.

The new research protocol using vervets appears more analogous to how ALS develops in humans, Dr. Davis said, compared to historic models using rodents. When he and colleagues gave the vervets a toxin produced by blue-green algae known as β-N-methylamino-L-alanine or BMAA, they developed pathology that closely resembles how ALS affects the spinal cords in humans.

When a group of these animals were fed L-serine together with BMAA for 140 days, the strategy was protective – the vervets showed significantly reduced signs of protein inclusions in spinal cord neurons and a decrease in pro-inflammatory microglia. The results were published on Thursday, February 20 at 5 a.m. EST in the prestigious Journal of Neuropathology & Experimental Neurology.

"The big message is that dietary exposure to this cyanobacterial toxin triggers ALS-type pathology, and if you include L-serine in the diet, it could slow the progression of these pathological changes," Dr. Davis said.

"I was surprised at how close the model mirrored ALS in humans," he added. Beyond looking at changes in the brain, "When we looked at the spinal cord, that was really surprising." The investigators observed changes specific to ALS seen in patients, including presence of intracellular occlusion such as TDP-43 and other protein aggregates.

Walter G. Bradley D.M., F.R.C.P., founder of the ALS Clinical and Research Center at the University of Miami Miller School of Medicine, said: "ALS is a progressive neurological disease, also known as Lou Gehrig's disease, causing progressive limb paralysis and respiratory failure. There is a great unmet need for effective therapies in this disease. After clinical trials of more than 30 potential drugs to treat ALS, we still have only two that slow the disease progression."

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ALS can rapidly progress in some people, leading to death in 6 months to 2 years after diagnosis. For this reason, it is difficult to enroll people in clinical trials, a reality that supports development of a corresponding animal model, Dr. Davis said.

In addition, prevention remains essential. "This is a pre-clinical model, which is really the most important type of model, because once people have full-blown disease, it's hard to reverse or slow its progression," he added.

The research builds on earlier findings from Dr. Davis and colleagues in a 2016 study that demonstrated cyanotoxin BMAA can cause changes in the brain that resemble Alzheimer's disease in humans, including neurofibrillary tangles and amyloid deposits.

Even with the promise of L-serine, the researchers note there is a bigger picture to their new ALS animal model. "Other drugs can also be tested, making this very valuable for clinical affirmation," Davis said.

The research also has implications for Florida, as BMAA comes from harmful blue-green algae blooms, which have become more common in the summer months in Florida.

According to Larry Brand, Ph.D., professor of marine biology at the Rosenstiel School at the University of Miami, "We have found that the BMAA from these blooms has biomagnified to high concentrations in South Florida aquatic food chains, thus our seafood."

We are very curious about how BMAA affects individuals in South Florida. That's our next step."

Dr. David A. Davis, Ph.D., lead author

Future research could attempt to answer multiple questions, including: How common is BMAA in local seafood? What are the risks of exposure through exposure to aerosolized cyanotoxins? Is there a specific group of people who are more vulnerable from this exposure to developing diseases like Alzheimer's and ALS?

The current research would not have been possible, Dr. Davis said, without interdisciplinary collaboration both inside and outside the University of Miami. Another essential factor is the "very unique research environment" in the UM Department of Neurology. For example, the Brain Endowment Bank allows Miller School researchers access to other investigators and to essential research material.

Source:

University of Miami Miller School of Medicine

Journal reference:

Davis, D.A., et al. (2020) L-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND. Journal of Neuropathology & Experimental Neurology. doi.org/10.1093/jnen/nlaa002.