As one of four data generation projects funded by NIH’s Bridge2AI, this multi-institution project – co-led by the University of South Florida and Weill Cornell Medicine – will bring together medical, voice, AI, engineering, and ethics experts to create a human voice database using privacy-preserving AI, giving doctors a new tool for diagnosing conditions known to have associations with voice alterations.

Tampa FL (Sept 13, 2022) – Artificial intelligence may soon help doctors diagnose and treat diseases, including cancer and depression, based on the sound of a patient’s voice, as 12 leading research institutions launch a landmark National Institutes of Health-funded academic project that may establish voice as a biomarker used in clinical care.

The University of South Florida in Tampa, FL, is the lead institution on the project in collaboration with Weill Cornell Medicine in New York City, 10 other institutions in the United States and Canada, and French-American AI biotech startup Owkin. The first year of the project includes $3.8 million from the NIH, with subsequent funding over the following three years contingent upon annual NIH appropriations by Congress that could bring the overall award to $14 million.

Called Voice as a Biomarker of Health, the project is one of several recently funded by the NIH Common Fund’s Bridge2AI program, which is designed to use AI to tackle complex biomedical challenges. The voice project will aim to build an ethically sourced database of diverse human voices while protecting patient privacy. Using this data, machine learning models will be trained to spot diseases by detecting changes in the human voice, which could empower doctors with a low-cost diagnostic tool to be used alongside other clinical methods.

Based on the existing literature and ongoing research, the research team has identified five disease cohort categories for which voice changes have been associated with specific diseases with well-recognized unmet needs. Data collected for this project will center on the following disease categories:

• Voice disorders: (laryngeal cancers, vocal fold paralysis, benign laryngeal lesions)
• Neurological and neurodegenerative disorders (Alzheimer’s, Parkinson’s, stroke, ALS)
• Mood and psychiatric disorders (depression, schizophrenia, bipolar disorders)
• Respiratory disorders (pneumonia, COPD)
• Pediatric voice and speech disorders (speech and language delays, autism)

Although preliminary work with voice data has been promising, limitations to integrating voice as a biomarker in clinical practice have been linked to small datasets, ethical concerns around data ownership and privacy, bias and lack of diversity of the data. To solve these, the Voice as a Biomarker of Health project is creating a large, high-quality, multi-institutional and diverse voice database that is linked to identity-protected/unidentifiable biomarkers from other data, such as demographics, medical imaging and genomics. Federated learning technology – a novel AI framework that allows machine learning models to be trained on data without the data ever leaving its source – will be deployed across multiple research centers by Owkin to demonstrate that cross-center AI research can be conducted while preserving the privacy and security of sensitive voice data.

Supported by AI experts, bioethicists and social scientists, the project aims to transform our fundamental understanding of diseases and introduce a revolutionary new method of diagnosing and treating diseases into clinical settings. As the human voice is low-cost, easy to store and readily available, diagnosing diseases through the voice using AI could prove a transformative step in precision medicine and accessibility.

Yael Bensoussan, MD, from USF Health Morsani College of Medicine, is a co-principal investigator for the NIH’s Bridge2AI, a multi-institution project. 

Voice as a Biomarker of Health is being co-led by Dr Yaël Bensoussan, MD, from USF Health Morsani College of Medicine and Olivier Elemento, PhD from Weill Cornell Medicine, who are co-principal investigators for the project. The project also includes lead investigators from 10 other universities in North America; Alexandros Sigaras and Anaïs Rameau (Weill Cornell Medicine), Maria Powell (Vanderbilt University Medical Center), Ruth Bahr and Gaetane Michaud (USF Health Morsani College of Medicine),  Alistair Johnson (Hospital for Sick Children), Philip Payne (Washington University in St. Louis), David Dorr (Oregon Health & Science University), Jean-Christophe Belisle-Pipon (Simon Fraser University), Vardit Ravitsky (University of Montreal), Satrajit Ghosh (Massachusetts Institute of Technology), Kathy Jenkins (Boston Children’s Hospital), Frank Rudzizc (University of Toronto) and Jordan Lerner-Ellis (Sinai Health). AI startup Owkin is deploying its federated learning technology across multiple research institutions to protect the security and privacy of sensitive voice data.

“Voice has the potential to be a biomarker for several health conditions,” said Dr. Bensoussan, assistant professor in the Department of Otolaryngology and director of USF Health Voice Center at the USF Health Morsani College of Medicine. “Creating an effective framework that incorporates huge datasets using the best of today’s technology in a collaborative manner will revolutionize the way that voice is used as a tool for helping clinicians diagnose diseases and disorders.”

“The potential for using voice and sounds together with advanced AI algorithms to accurately diagnose certain diseases is incredible. Our future findings could lead to a revolution in health care where continuous voice monitoring could alert physicians earlier than currently possible to certain conditions, such as infections or neurological diseases,” said Dr. Elemento, director of the Englander Institute for Precision Medicine and a professor of physiology and biophysics at Weill Cornell Medicine.

Olivier Elemento, PhD, from Weill Cornell Medicine, is a co-principal investigator for the NIH’s Bridge2AI, a multi-institution project.

“By using AI to analyze minute changes in the human voice, we aim to help doctors to diagnose and treat diseases ranging from cancer to depression. Vocal biomarkers are set to play an increasingly important role in healthcare. We are excited to be using federated learning, our privacy-preserving AI framework, to connect the medical world together in the pursuit of improving outcomes for patients,” said Thomas Clozel MD, co-founder and CEO of Owkin.

This project is supported by the National Institutes of Health award number: OT2OD032720.

About USF Health

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the Taneja College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and USF Health’s multispecialty physicians group. The University of South Florida is a high-impact global research university dedicated to student success. Over the past 10 years, no other public university in the country has risen faster in U.S. News and World Report’s national university rankings than USF. For more information, visit health.usf.edu

About Weill Cornell Medicine
Weill Cornell Medicine is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of Weill Cornell Medicine — faculty from Weill Cornell Medical College, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Physician Organization — are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Located in the heart of the Upper East Side’s scientific corridor, Weill Cornell Medicine’s powerful network of collaborators extends to its parent university Cornell University; to Qatar, where Weill Cornell Medicine-Qatar offers a Cornell University medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell Medicine faculty provide exemplary patient care at NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian Westchester Behavioral Health Center, NewYork-Presbyterian Lower Manhattan Hospital, NewYork-Presbyterian Queens and NewYork-Presbyterian Brooklyn Methodist Hospital. Weill Cornell Medicine is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

Media contacts:

• University of South Florida: Allison Long: allison65@usf.edu
• Weill Cornell Medicine: Eliza Powell: elp4014@med.cornell.edu
• Owkin: Alexander Blackburn: blackburn@owkin.com
• NIH: Rachel Britt: cfcomms@nih.gov

Photos: Yael Bensoussan, MD (Allison Long/USF Health) Olivier Elemento, PhD (WCM /Travis Curry)

USF Health microbiome expert Hariom Yadav, PhD, has received a grant from the National Institute on Aging to help determine if a common medication can restore microbiome diversity in older patients who have a form of heart failure and, thus, prevent the subsequent problems that tend keep these patients inactive and cause their conditions to worsen.

Hariom Yadav, PhD, was recently recruited to lead the USF Microbiome Research Center and his research focuses on the gut-brain connection (gut-brain axis) in relation to cognitive function.

Dr. Yadav, associate professor in the Division of Digestive Diseases and Nutrition for the Department of Neurosurgery and Brain Repair and Internal Medicine in the USF Health Morsani College of Medicine and director of the USF Center for Microbiome Research in the Microbiomes Institute, is a co-principal investigator and is working with co-principal investigator and project lead Dalane Kitzman, MD, at Wake Forest University in Winston-Salem, North Carolina.

The 3-year NIH consortium project research, which will include patients diagnosed with heart failure with preserved ejection fraction (HFpEF), is titled “Repurposing of Metformin for Older Patients with HFpEF.”

Preclinical studies show that gut barriers, including mucin production, are reduced in older gut and cause ‘leaky gut’, which allows certain antigens to diffuse into blood circulation, thus causing systemic inflammation. Preliminary data also suggest that older HFpEF patients have markedly reduced microbiome diversity, including reduced production of beneficial metabolites such as butyrate, which maintain health and gut wall integrity, and may help reduce leaky gut.

Metformin prescription bottle. Metformin is a generic medication name and label was created by photographer.

Metformin is a generic FDA-approved medication used for diabetes. Earlier studies, including research in Dr. Yadav’s lab, shows that metformin decreases leaky gut by improving microbial diversity and increasing intestinal wall mucin production thereby reducing systemic inflammation and improving physical function in lab model studies.

This new study seeks to translate these findings to determine if metformin improves microbiome diversity, reduces leaky gut, and reduces the inflammation associated with HFpEF in patients, a common condition in older people, particular older women.

“Earlier research suggests that metformin can inhibit a root cause of systemic inflammation – leaky gut – and its adverse consequences which are highly relevant to HFpEF, including exercise intolerance, a known barrier for HFpEF patients for staying active,” Dr. Yadav said. “We propose to test repurposing of metformin, a promising medication for improving heart failure outcomes by improving gut leakiness and microbial diversity, and that metformin will restore gut microbiome diversity and increase gut wall mucin, which in turn will reduce leaky gut and systemic inflammation and improve physical function for HFpEF patients.”

This new study is a randomized, blinded, placebo-controlled trial over 20 weeks in 80 non-diabetic HFpEF patients age 60 and older. The Wake Forest and Atrium Health team will coordinate the patients, measuring physical function, provide a quality of life questionnaire, and collect stool and blood samples. The team in Dr. Yadav’s lab will examine the samples and measure microbiome diversity and the key markers of leaky gut and of inflammation.

This study is supported by the National Institute on Aging of the National Institutes of Health under Award Number U01AG076928.

Dr. Yadav is conducting similar research associated with leaky gut and inflammation, including their connections to Alzheimer’s disease and other related dementias.

Tampa FL (June 8, 2022) – The University of South Florida received $3.2 million from the National Institute on Aging to investigate if Alzheimer’s disease can be detected early through simple blood tests.

The new funding dovetails with a $44.4 million, five-year NIH grant awarded to USF last year testing whether computerized braining training can reduce dementia risk in older adults. Called the Preventing Alzheimer’s with Cognitive Training (PACT) study, it is the largest primary prevention trial to date designed to rigorously test the effectiveness of computer-based training to protect against MCI and dementias.

Participants enrolling in the PACT study can also enroll in the study investigating whether a simple blood test can detect dementia. The PACT study will work with the National Centralized Repository for Alzheimer’s Disease and Related Dementias to analyze blood samples collected from study participants.

“We need another 2000 healthy older adults to volunteer for the PACT study. We are very grateful to the 1800 volunteers from Tampa Bay who have already joined our fight against Alzheimer’s disease by enrolling in PACT.” said principal investigator Jerri Edwards, PhD, a professor of psychiatry and behavioral neurosciences in the USF Health Morsani College of Medicine. “Participants will now not only be contributing to our work on how to possibly prevent dementia, but also advancing efforts to develop blood tests for early detection of the disease.”

Jerri Edwards, PhD, professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine, is USF site principal investigator for the PACT study.

Currently, diagnosing dementia such as Alzheimer’s disease requires expensive PET scans or invasive cerebrospinal fluid samples. This new study will contribute to research working toward developing simple blood tests to improve existing methods.

Launched last year, the PACT study continues to recruit participants, seeking healthy older adults to volunteer for the landmark study examining whether computerized brain training exercises can reduce the risk of cognitive impairment and dementia such as Alzheimer’s disease. PACT study volunteers should be age 65 or older with no signs of cognitive impairment or dementia. Those accepted into the study will participate in initial testing at a PACT location at the USF Tampa or St. Petersburg campuses or at Reliance Medical in Lakeland. The PACT study is also being conducted by partner sites at Clemson University, University of Florida, University of North Florida, and Duke University.

The USF PACT study concentrates on the effectiveness of computerized programs, or brain games, for preventing dementia such as Alzheimer’s disease. These computerized training exercises are designed to potentially enhance mental quickness and visual attention. At the end of the trial, the scientists will examine the blood samples from willing participants and determine which specific blood-based biomarkers predict Alzheimer’s disease, the severity of the disease, and/or responsiveness to treatment.

The PACT study is supported by the National Institute on Aging, part of the National Institutes of Health (NIH), grant number R01AG070349. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

More information is available at the PACT study website, pactstudy.org, or by calling 813-974-6703.

USF Health-UT Southwestern Medical Center preclinical study suggests inhibiting PPP1R3G/PP1γ may protect against tissue damage from heart attacks, other diseases linked to inflammation

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TAMPA, Fla. (Feb. 16, 2022) – Cell death plays an important role in normal human development and health but requires tightly orchestrated balance to avert disease. Too much can trigger a massive inflammatory immune response that damages tissues and organs. Not enough can interfere with the body’s ability to fight infection or lead to cancer.

Zhigao Wang, PhD, associate professor of cardiovascular sciences at the University of South Florida Health (USF Health) Morsani College of Medicine, studies the complex molecular processes underlying necroptosis, which combines characteristics of apoptosis (regulated or programmed cell death) and necrosis (unregulated cell death).

During necroptosis dying cells rupture and release their contents. This sends out alarm signals to the immune system, triggering immune cells to fight infection or limit injury. Excessive necroptosis can be a problem in some diseases like stroke or heart attack, when cells die from inadequate blood supply, or in severe COVID-19, when an extreme response to infection causes organ damage or even death.

A new preclinical study by Dr. Wang and colleagues at the University of Texas Southwestern Medical Center identifies a protein complex critical for regulating apoptosis and necroptosis — known as protein phosphatase 1 regulatory subunit 3G/protein phosphatase 1 gamma (PPP1R3G/PP1γ, or PPP1R3G complex). The researchers’ findings suggest that an inhibitor targeting this protein complex may help reduce or prevent excessive necroptosis.

The study was reported Dec. 3, 2021, in Nature Communications.

Zhigao Wang, PhD, associate professor of cardiovascular sciences, in his laboratory at the USF Health Heart Institute. Images on the monitor depict two types of cell death: apoptosis (left) and necroptosis. — Photo by Allison Long, USF Health Communications

“Cell death is very complicated process, which requires layers upon layers of brakes to prevent too many cells from dying,” said study principal investigator Dr. Wang, a member of the USF Health Heart Institute. “If you want to protect cells from excessive death, then the protein complex we identified in this study is one of many steps you must control.”

Dr. Wang and colleagues conducted experiments using human cells and a mouse model mimicking the cytokine storm seen in some patients with severe COVID-19 infection. They applied CRISPR genome-wide screening to analyze how cell function, in particular cell death, changes when one gene is knocked out (inactivated).

Receptor-interacting protein kinase (RIPK1) plays a critical role in regulating inflammation and cell death. Many sites on this protein are modified when a phosphate is added (a process known as phosphorylation) to suppress RIPK1’s cell death-promoting enzyme activity. How the phosphate is removed from RIPK1 sites (dephosphorylation) to restore cell death is poorly understood. Dr. Wang and colleagues discovered that PPP1R3G recruits phosphatase 1 gamma (PP1γ) to directly remove the inhibitory RIPK1 phosphorylations blocking RIPK1’s enzyme activity and cell death, thereby promoting apoptosis and necroptosis.

Dr. Wang (back) and laboratory associate Ken Chen. — Photo by Allison Long, USF Health Communications

Dr. Wang uses the analogy of a car brake help explain what’s happening with the balance of cell survival and death in this study:  RIPK1 is the engine that drives the cell death machine (the car). Phosphorylation applies the brake (stops the car) to prevent cells from dying. The car (cell death machinery) can only move forward if RIPK1 dephosphorylation is turned on by the PPP1R3G protein complex, which releases the brake.

“In this case, phosphorylation inhibits the cell death function of protein RIPK1, so more cells survive,” he said. “Dephosphorylation takes away the inhibition, allowing RIPK1 to activate its cell death function.”

The researchers showed that a specific protein-protein interaction – that is, PPP1R3G binding to PP1γ — activates RIPK1 and cell death. Furthermore, using a mouse model for “cytokine storm” in humans, they discovered knockout mice deficient in Ppp1r3g were protected against tumor necrosis factor-induced systemic inflammatory response syndrome. These knockout mice had significantly less tissue damage and a much better survival rate than wildtype mice with the same TNF-induced inflammatory syndrome and all their genes intact.

Overall, the study suggests that inhibitors blocking the PPP1R3G/PP1γ pathway can help prevent or reduce deaths and severe damage from inflammation-associated diseases, including heart disease, autoimmune disorders and COVID-19, Dr. Wang said. His laboratory is working with Jianfeng Cai, PhD, a professor in the USF Department of Chemistry, to screen and identify peptide compounds that most efficiently inhibit the PPP1R3G protein complex. They hope to pinpoint promising drug candidates that may stop the massive destruction of cardiac muscle cells caused by heart attacks.

The research was supported by grants from the Welch Foundation and the National Institute of General Medical Sciences, a part of the National Institutes of Health.

Graphic created with Biorender app by Zhigao Wang, USF Health Heart Institute.

USF Health research discovers APC limits heart damage by preventing excessive loss of endothelial protein C receptors on the cardiac muscle cell membrane

TAMPA, Fla. (Jan. 31, 2022) — A University of South Florida Health (USF Health) preclinical study offers molecular insight into how activated protein C (APC) may improve aging patients’ tolerance to reperfusion injury – a potentially adverse effect of treatment for ischemic heart disease.

The research, published online Dec. 21 in Circulation Research, suggests that drugs derived from APC may limit ischemia and reperfusion-induced heart damage (reperfusion injury for short) and thereby help preserve cardiac function in older hearts.

Advanced age is a major risk factor for ischemic heart disease, often caused by a buildup of plaques in coronary arteries that narrows the vessels and restricts the supply of oxygenated blood to the heart. This “hardening of the arteries” can eventually trigger a heart attack.

Blood thinners, clot-buster medications, and other drugs, as well as procedures such as coronary artery bypass surgery and balloon angioplasty, are commonly used to restore blood flow to oxygen-starved (ischemic) heart muscle tissue. Paradoxically, especially in older patients, these necessary revascularization treatments can worsen cellular dysfunction and death around the site already damaged by a heart attack, or coronary artery disease. No effective treatments currently exist to prevent age-related reperfusion injury.

“Our research focuses on trying to determine why older hearts are at greater risk for reperfusion injury than younger hearts,” said lead author Di Ren, PhD, a research associate in the Department of Surgery, USF Health Morsani College of Medicine. “Our goal is to find targeted therapeutic strategies to help older people improve their resistance to the pathological condition of ischemia and reperfusion stress.”

“The preliminary evidence in this paper suggests that treatment with activated protein C has the potential to strengthen the cardiac tolerance of aging patients to reperfusion injury from surgery, minimally invasive procedures, or drugs, and (thereby) increase heart attack prevention or survival,” said the study’s principal investigator Ji Li, PhD, a professor of surgery at the USF Health Heart Institute.

Di Ren, PhD, a research associate in the USF Health Department of Sugery, was the Circulation Research paper’s lead author.

APC, a protein circulating in blood, has both anticoagulant (blood clot prevention) and anti-inflammatory functions that can help protect cells from disease and injury. Endothelial protein C receptor (EPCR) – located both on cells lining blood vessels and on the surface of cell membranes, including heart muscle cells – is associated with increased APC production and regulates APC’s subsequent cell signaling (or cell communication).

In this mouse model study, the researchers analyzed how APC exerts cardiac protection during ischemia and reperfusion. The groups of mice observed included young and old “wild-type” mice with all their genes intact, and young “knock-in” EPCR R84A/R84A mice genetically modified to make their EPCR receptors incapable of interacting with the APC protein as well as their wild-type littermates without the EPCR R84A/R84A mutation.

Naturally occurring APC or one of two laboratory-engineered APC derivatives were administered to the mice with heart attack-induced ischemia before reperfusion. One derivative (compound APC-2Cys) selectively activated a signaling pathway to promote cell protection without inhibiting blood clotting (coagulation). The other derivative (compound APC-E170A) selectively triggered a signaling pathway promoting only anticoagulation.

Ji Li, PhD, a professor of surgery at the USF Health Heart Institute, was the study’s principal investigator. — Photo by Allison Long, USF Health Communications

Among the team’s key preclinical findings:

— The stress of Ischemia and reperfusion injury induced “shedding” of EPCRs in young and old wild-type mice – that is, a greater number of these receptors were cut from the heart muscle cell membrane and then moved into the bloodstream. This EPCR shortage (deficiency) in the heart can impair activated protein C signaling critical for favorably regulating energy metabolism and anti-inflammatory responses, preventing cell death, and stimulating other activities needed to protect cardiac muscle cells.

— While the hearts of the old and young wild-type mice both showed EPCR shedding, older hearts experienced a more severe EPCR deficiency and decline in APC signaling activity in response to reperfusion injury. No APC signaling was detected in the EPCRR84A/R84A mice, because APC was blocked from binding to the cell membrane receptor.

— Administering APC or its derivatives helped reduce heart damage inflicted by ischemia and reperfusion, particularly in the old mice. Digging deeper, the researchers discovered that by stabilizing (maintaining) EPCR on the cardiac cell membrane, APC strengthens the aging heart’s resistance both to heart attack-related ischemia and to injury associated with restoring coronary artery blood flow.

— Furthermore, APC and the APC-2Cys signaling derivative, but not the APC-E170A anticoagulant-selective signaling (a potential bleeding risk), helped preserve cardiac function. All cardioprotective effects of APC were weaker in young mice in which EPCR was eliminated; their hearts looked and performed like that of older mice.

— The researchers detailed how APC treatments improve cardiac function by regulating both acute (short-term) and chronic (longer-term) metabolic pathways. They demonstrated that enzyme AMPK (AMP-activated protein kinase) mediates an acute adaptive response to cardiac stress immediately following heart attack, while enzyme AKT (protein kinase B) regulates chronic metabolic adjustments to reperfusion stress over time. APC treatment led to better enzyme activity and more efficient energy balance needed to contract cardiac muscle cells and pump blood from the heart to the rest of the body.

“APC is beneficial for ischemia-reperfusion injury both in the acute and chronic stages, so appropriate APC derivatives might be used both as preventive and therapeutic drugs,” Dr. Li said.

Activated protein C (green) interacts with endothelial protein C receptors (red) to form APC/EPCR binding complex (yellow) and stabilize subsequent EPCR-regulated signaling in heart muscle cells under hypoxia-reperfusion stress.  Image courtesy of Ji Li Laboratory, USF Health; first appeared in Circulation Research; DOI: 10.1161/CIRCRESAHA.121.319044

The USF Health Heart Institute researchers collaborated with scientists from Scripps Research Institute, McMaster University (Canada), and the Oklahoma Medical Research Foundation.

Their work was funded by grants from the National Institutes of Health, both the NIGMS and NHLBI.

Development of autoimmunity at an early age associated with more aggressive form of the disease in genetically susceptible children, a USF Health-led study suggests

TAMPA, Fla. (Oct. 21, 2021) — New findings from the international The Environmental Determinants of Diabetes in the Young (TEDDY) study add to the growing body of evidence indicating that type 1 diabetes is not a single disease. The presentation and, perhaps, cause of autoimmune diabetes differs among genetically high-risk children, the research suggests.

In a cohort study published July 22 in Diabetologia, lead author Jeffrey Krischer, PhD, director of the Health Informatics Institute at the USF Health Morsani College of Medicine, and TEDDY colleagues compared the characteristics of type 1 diabetes diagnosed in children before vs. after age 6.  The paper’s senior author was Beena Akolkar, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

“Our results underscore the importance of taking into account the age at development of multiple autoantibodies when evaluating risk factors for progression to a diabetes diagnosis,” said lead author Dr. Krischer, a Distinguished University Health Professor and co-chair for the National Institutes of Health-funded TEDDY consortium. “When the changing picture of autoantibody presentation is considered, it appears type 1 diabetes at an early age is a more aggressive form of the disease.”

In type 1 diabetes, a misdirected immune response attacks and destroys insulin-producing beta cells in the healthy person’s pancreas – a process occurring over months or many years. Four autoantibodies directed against the pancreatic β-cells — glutamic acid decarboxylase autoantibody (GADA), insulin autoantibody (IA), insulinoma-associated-protein-2 autoantibody (IA2-2A), and zinc transporter 8 autoantibody (ZnT8A) – are thus far the most reliable biological indicators of early type 1 diabetes, before symptoms appear. Not all children who test positive for one or more autoantibodies progress to a diagnosis of type 1 diabetes, which requires lifelong administration of insulin to control blood sugar levels and reduce health complications.

Over the last decade, TEDDY researchers have learned more about how the order, timing and type of autoantibodies can help predict which genetically susceptible children are most likely to get type 1 diabetes as they age.

For this multisite study in the U.S. and Europe, the researchers analyzed data from 8,502 children, all at genetically high risk for developing autoimmunity and type 1 diabetes. The children were followed from birth to a median of 9 years. Over this period, 328 study participants (3.9%) progressed from a presymptomatic stage in which autoantibodies first appeared in their circulating blood (signaling initial autoimmunity) to the onset of symptomatic type 1 diabetes.

Study lead author Jeffrey Krischer, PhD, directs the USF Health Informatics Institute and is co-chair for the National Institutes of Health-funded TEDDY consortium.

Half of the 328 participants (2.0%) were diagnosed before age 6, while the other half (1.9%) developed diabetes between ages 6 and 12. The aim was to determine whether the younger group diagnosed with type 1 diabetes differed from the older group, which would suggest that a different form of type 1 diabetes emerges in children as they grow older.

Among the findings:

• As expected, TEDDY participants who progressed to diabetes between ages 6 and 12 were more likely to have first-appearing autoantibodies to the pancreatic enzyme glutamic acid decarboxylase (GAD autoantibodies), while first-appearing insulin autoantibodies (IA antibodies) were much more common in younger children developing the disease.
• The rate of progression to type 1 diabetes was slower if multiple (two or more) autoantibodies appeared after age 6 than if they were present before age 6.
• The significant association of country of origin with diabetes risk found in the younger group declined in the older group. Conversely, the link between certain genotypes and a higher likelihood of developing diabetes significantly increased in the older children.
• Among children 6 and older with multiple autoantibodies, family history did not appear to play a role in whether the child progressed to type 1 diabetes.

“Much of the observed differences in the relationship between genes and environmental exposures can be explained by the age at appearance of autoantibodies,” Dr. Krischer said. “That is important, because it means factors linked with diabetes risk need to be conditioned on age to be properly understood. There may be different environmental exposures occurring at different ages that trigger autoimmunity, or the same environmental trigger may act differently at different ages.”

The research was funded by grants from the NIDDK and several other NIH institutes, JDRF, and the Centers for Disease Control and Prevention (CDC); and supported in part by NIH/NCATS Clinical and Translational Science Awards.

USF Health-led research validates crucial role of the spleen in cardiac healing, suggests targeting lipid mediator S1P may offer a promising heart failure treatment

Tampa, FL (Aug. 23, 2021) — Although we can survive without a spleen, evidence continues to mount that this abdominal organ plays a more valuable role in our physiological defenses than previously suspected.

“The spleen holds a whole army of immune cells and signaling molecules that can be rapidly mobilized to respond whenever a major injury like a heart attack or viral invasion occurs,” said Ganesh Halade, PhD, an associate professor of cardiovascular sciences at the University of South Florida Health (USF Health) Morsani College of Medicine.

Principal investigator Ganesh Halade, PhD, is an associate professor of cardiovascular sciences at the USF Health Morsani College of Medicine and a member of the college’s Heart Institute. | Photo by Allison Long, USF Health Communications

Dr. Halade led a new preclinical study that analyzed the interactions of the lipid mediator sphingosine-1-phosphate (S1P) in the spleen and heart during the transition from acute to chronic heart failure. The researchers discovered new cardiac repair mechanisms to help shed light on spleen-heart coordination of physiological inflammation in a mouse model of heart failure.

The study appeared online August 20 in the American Journal of Physiology- Heart and Circulation.

“Simply put, we showed that the spleen and the heart work together through S1P for cardiac repair,” said principal investigator Dr. Halade, a member of the USF Health Heart Institute. “Our study also suggests that early detection of little or no S1P levels after a heart attack and targeted activation of this bioactive lipid mediator may provide a cardioprotective treatment for patients at high risk of heart failure.”

Dr. Halade and colleagues have defined connections between fatty acids, dysfunctional inflammation control, and heart failure. His laboratory focuses on discovering ways to prevent, delay or treat unresolved inflammation after a heart attack. In this latest study, the researchers turned their attention to where S1P is produced and its role in cardiac repair.

S1P is a lipid mediator dysregulated during inflammatory responses, including heart failure. Moreover, several groups have demonstrated the potential significance of this signaling molecule as a treatment target for heart failure triggered by heart attack and ischemia-reperfusion injury.

People can survive without a spleen, a fist-sized abdominal organ that helps fight infection. But its removal (due to abdominal trauma, or certain medical conditions) has been linked to an increased risk of death from ischemic heart disease.

The USF Health study captured time-dependent movement of S1P from the spleen through circulating blood plasma to the heart. The work was the first to quantify interactions between S1P and S1P receptor 1 (S1PR1) during the progression from acute to chronic heart failure, Dr. Halade said.

The researchers defined S1P/S1PR1 signaling in both mice and humans with heart failure after a heart attack. The otherwise young, healthy “risk-free” mice had no variable cardiovascular risk factors such as obesity, diabetes, hypertension, and aging commonly seen in a clinical setting. The researchers correlated the physiological data from the cardiac-repair mouse model experiments with what they observed in pathologically failing human hearts.

Among their key findings:

• Cardiac-specific S1P and S1PR1 levels were reduced in patients with ischemic heart failure.
• In the risk-free mice, physiological cardiac repair was facilitated by activation of S1P in the heart and the spleen. S1P/S1PR1 signaling increased in both organs from acute through chronic heart failure, helping to promote cardiac repair after heart attack.
• Increased plasma S1P indicates cardiac repair in the acute phase of heart failure.
• Selective activation of the S1P receptor in macrophages (immune cells that that help clear inflammation and guide tissue repair) suppressed biomarkers of inflammation and accelerated biomarkers of cardiac healing in mouse cells.

“This study provides another example that the spleen should not be underestimated, because it contributes to the foundation of our immune health as well as the root cause of inflammatory diseases, including cardiovascular disease,” Dr. Halade said.

The research was supported by grants from the National Institutes of Health and the U.S. Department of Veterans Affairs.  The University of South Florida team worked with collaborators at the University of Alabama at Birmingham and Hokkaido University, Japan.

Targeting the gene Foxo1 may offer an early treatment approach for hereditary lymphedema, USF Health preclinical study reports

Principal investigator Ying Yang, PhD, is an assistant professor of molecular pharmacology and physiology in the USF Health Morsani College of Medicine and a member of the college’s Heart Institute. | Photo by Allison Long, USF Health Communications

Tampa, FL (Aug. 9, 2021) — A University of South Florida (USF Health) preclinical study unexpectedly identified the gene Foxo1 as a potential treatment target for hereditary lymphedema. The research, published July 15 in The Journal of Clinical Investigation, was done with colleagues from Tulane University and the University of Missouri.

Lymphedema — a chronic condition in which lymphatic (lymph) fluid accumulates in soft tissue under the skin, usually in the arms and legs — causes minor to painfully disfiguring swelling. Primary, or hereditary, lymphedema is rare, present at birth and caused in part by genetic mutations that regulate normal lymphatic valve development. Secondary, or acquired, lymphedema is caused by damage to the lymphatic system from surgery, radiation therapy, trauma, or parasitic infection. In the U.S., lymphedema most commonly affects breast cancer patients, with prevalence ranging from 10 to 40% after lymph node removal and radiation therapy.

While lymphedema can be managed with massage and compression garments, no treatment exists to address its underlying cause: the build-up of fluid that eventually backs up in the lymph system like an overflowing sink with a blocked drain. This stagnant lymph triggers an inflammatory response that can induce connective and fatty tissue to form and harden the skin, restricting movement and increasing the risk of recurrent infections.

Green immunostained image of a lymphatic vessel with one valve in the center and another in the top left corner. To the upper right of the lymph vessel is a large vein. | Photo courtesy of Joshua Scallan, PhD.

“The later fibrosis stage of lymphedema cannot be massaged away,” said study principal investigator Ying Yang, PhD, assistant professor of molecular pharmacology and physiology at the USF Health Morsani College of Medicine. “Targeting lymph valves early in the disease is one critical aspect in identifying an effective treatment for lymphedema. If the disease progresses too far, it’s difficult to reverse.”

Valve loss or dysfunction that disrupts the flow of lymph fluid is strongly associated with lymphedema in patients. But no one has discovered whether new valves can be grown or if defective ones can be fixed.

The USF Health-led study shows that both are possible.

Dr. Yang’s group hypothesized that the protein encoded by the gene Foxo1 plays a key role in lymph valve formation based on an earlier USF Health discovery of cell signaling processes controlling formation of lymph valves. The researchers showed that deleting a single gene — lymphatic vessel-specific Foxo1 — promoted the growth of markedly more valves in both young postnatal mice and adult mice than in control littermates without Foxo1 deletion. Furthermore, deleting Foxo1 in a mouse model mimicking human lymphedema-distichiasis syndrome fully restored the both the number of valves and valve function.

Dr. Yang (left) and with biologist Luz Knauer | Photo by Allison Long, USF Health Communications

“It was exciting to see that Foxo1 is the only gene so far reported that, when deleted, induces more lymphatic valves to form, instead of inhibiting valve growth,” said Dr. Yang, a member of the USF Health Heart Institute. “We actually reversed valve loss and repaired the structure and function of defective valves in a genetic mutation model of lymphedema…That type of discovery makes a study clinically relevant.”

The lymphatic circulatory system – a parallel of the blood vessel circulatory system – helps maintain healthy fluid balance in the body by collecting and controlling the flow of extra lymph fluid that leaks from tissue. This complex network propels watery lymph fluid carrying proteins, nutrients and toxin-destroying immune cells through the body in one direction before returning the fluid to circulating blood. Small valves inside lymph vessels open and close in response to force exerted by the lymph fluid, moving it forward and preventing backward flow into tissues.

Dr. Yang in her lab where she researches lymphedema, which in the U.S. most commonly occurs in some breast cancer patients after lymph node removal and radiation therapy. Some of the research is light sensitive and must be conducted in near darkness. | Photo by Allison Long, USF Health Communications

Among the key study findings:

• The protein FOXO1 (encoded by gene Foxo1) inhibits lymph valves from developing by suppressing many genes, which collectively contribute to the multi-step process of making a mature valve. FOXO1 behaves like a brake on a set of valve-forming genes, Dr. Yang said. “Once the brake is removed, all those genes can now be expressed so that new valves can successfully grow.”

• Inactivation (knockout) of Foxo1 in lymphatic endothelial cells (LEC) of young postnatal mice promoted valve formation at multiple stages. Likewise, deleting LEC-specific Foxo1 in adult mice also increased valve formation, compared to control mice without the gene knockout.

• A mouse model of lymphedema-distichiasis syndrome had 50% fewer lymphatic valves and the remaining valves closed abnormally and exhibited fluid backflow. But when Foxo1 was deleted, the number of valves increased to the same levels as those in healthy control mice and the structure of defective valves was restored to normal. Further analysis showed that the loss of Foxo1 also significantly improved valve function in this mouse model of human primary lymphedema disease.

Photo by Allison Long | USF Health Communications

This study was supported by grants from the National Heart, Lung, and Blood Institute, a part of the National Institutes of Health. USF Health’s Joshua Scallan, PhD, was the lead author.

A previously validated gene profile in blood that predicts idiopathic pulmonary fibrosis mortality was repurposed to assess the likelihood of COVID-19 survival, a USF Health-led study reports

Tampa, FL (June 20, 2021) — A blood gene profile associated with a high risk of dying from a severe lung disease can also predict poor outcomes in patients with COVID-19, a multicenter retrospective study led by the University of South Florida Health (USF Health) demonstrated. The risk profile based on 50 genes could help customize how COVID-19 is treated, improve allocation of limited health care resources such as intensive care beds and ventilators, and potentially save lives.

Idiopathic pulmonary fibrosis (IPF), a disease of unknown cause, affects the lung interstitium or the space between the lung sacs and the bloodstream, leading to severe lung scarring. Severe COVID-19 can also damage the lung interstitium leading to severe lung scarring.

“Our study identified at the molecular level, a gene risk profile that predicts worse COVID-19 outcomes before the patient becomes severely ill,” said principal investigator Jose Herazo-Maya, MD, an associate professor and associate chief of pulmonary, critical care and sleep medicine at the USF Health Morsani College of Medicine. “That means every patient with COVID-19 could potentially get a blood test that could tell us if they are at high or low risk of dying… And if we know in advance who will likely end up in the ICU and who will likely do well recovering at home with appropriate monitoring, we can tailor our interventions to individual patients based on their level of risk.”

The USF Health study appeared online June 20 in EBioMedicine, a publication of THE LANCET. It builds upon previous genomic research by Dr. Herazo-Maya and colleagues at Yale School of Medicine. In 2017, they led an international team that studied and validated a gene expression signature in the blood that reliably forecasts the likelihood of IPF mortality. (Certain patients with lung scarring can live well for years, while others develop worsening disease and die quickly from IPF.)

The study’s principal investigator was Jose Herazo-Maya, MD, associate professor of medicine and associate division chief of USF Health Pulmonary, Critical Care and Sleep Medicine. | Photo by Allison Long,  USF Health Communications and Marketing

As the COVID-19 pandemic unfolded, “the basic question we had was ‘Can we repurpose the gene signature known to predict mortality in a fibrotic lung disease to predict mortality in those infected with a new coronavirus that can cause lung fibrosis as well?” said the EBioMedicine paper lead author Brenda Juan-Guardela, MD, assistant professor of medicine at the USF Health Morsani College of Medicine and medical director of Respiratory Care Services at Tampa General Hospital (TGH). “To the best of our knowledge, this study is the first to compare overlapping immune gene profiles in COVID-19 and IPF, which were remarkably similar.”

The USF Health-led team analyzed gene expression patterns of 50 genes known to predict IPF mortality in three COVID-19 cohorts and two IPF cohorts. The researchers used a molecular scoring system to distinguish between high versus low-risk gene profiles in all five cohorts.

Among their findings:

• In the COVID-19 validation cohorts, a 50-gene high risk profile was linked to greater risk of ICU admission, mechanical ventilation, and in-hospital death.
• The researchers also performed single-cell, gene expression analyses and identified specific immune cells — monocytes, neutrophils, and dendritic cells – as the primary source of gene expression changes in the high-risk, COVID-19 gene profile. This finding suggests COVID-19 and IPF may share common innate and adaptive immune responses that trigger lung scarring.
• The 50-gene risk profile in COVID-19 can also predicts mortality in IPF at the exact same threshold.

Lead author Brenda Juan-Guardela, MD, assistant professor of medicine at the USF Health Morsani College of Medicine and medical director of Respiratory Care Services at TGH

At TGH, Dr. Herazo-Maya treats previously hospitalized COVID-19 patients who come to the Center for Advanced Lung Disease with severe lung fibrosis; some are being evaluated for lung transplantation. “Even though coronavirus cases are dropping, that doesn’t mean all the patients will recover without complications,” he said. “We’re starting to see the damaging, long-term effects in the lungs of some COVID-19 survivors.”

While more studies are needed, researchers and clinicians may soon be able to apply the gene risk profiles to help advance the care of both COVID-19 and IPF patients, Dr. Herazo-Maya said. His laboratory is currently developing a blood test, based on these genes, that can be easily applied in clinical practice to predict poor disease outcomes.

Besides outcome prediction, the identification of 50-gene risk profiles may also have significant therapeutic potentials.  For example, a 10-day regimen of the steroid dexamethasone, a drug that suppresses the immune system, has been shown to increase survival of patients hospitalized with COVID-19. Immunosuppressant drugs have been essentially discontinued for IPF treatment because they increase mortality when given at high doses and in combination over long periods, Dr. Herazo-Maya said. “But perhaps we could investigate the use of dexamethasone or a similar steroid treatment for a short period of time in a subgroup of IPF patients with a 50-gene high risk profile, using the principle of precision or personalized medicine.”

The 50-gene high risk profile may also support the rationale to investigate the use of targeted IPF antifibrotic medications, which slow the rate of lung scarring, to prevent short and long-term sequelae of COVID-19, he added.

Heat maps depict clustering of COVID-19 subjects based on 50-gene risk profiles (High versus Low) determined by SAMS in Discovery (a) and Validation cohorts (b). The image, courtesy of Jose Herazo-Maya, first appeared online 20 June 2021 in EBioMedicine, Vol. 69. Full caption available for this Figure 1 at: www.sciencedirect.com/science/article/pii/S2352396421002322

USF Health’s Gaetane Michaud, MD, professor of medicine and chief of pulmonary, critical care and sleep medicine, was a paper coauthor. The research was supported by the Ubben Pulmonary Fibrosis Fund-USF Foundation, National Institute for Health Clinician Scientist Fellowship, Action for Pulmonary Fibrosis Mike Bray Fellowship, and the National Heart, Lung, and Blood Institute.

An international research team, including the USF Health Informatics Institute, created and validated a model with potential for early monitoring of infants at risk for T1D diabetes

Children (and adults) diagnosed with type 1 diabetes must have their blood glucose levels monitored, and take insulin shots or use an insulin pump every day to stay well.

TAMPA, Fla. (June 4, 2021) — Type 1 diabetes mellitis (T1D) is an autoimmune disease in which a misdirected immune system gradually destroys healthy pancreatic islet β cells, resulting in a deficiency of insulin. The exact cause of T1D remains unknown. However, β cell-reactive autoantibodies can be detected in circulating blood months to years before diagnosis, raising the possibility of intervening to stop or delay T1D before children develop the disease.

Monitoring the number, type, and concentration of autoantibodies appearing in the blood can help predict the long-term risk of progression to symptomatic T1D.

Now new findings suggest that measuring how patterns of gene expression in white blood cells change in children starting in infancy – before autoantibodies indicate an autoimmune reaction against the β cells – can predict earlier and more robustly which genetically-susceptible individuals will progress to T1D. The comprehensive international study included co-investigators from the University of South Florida Health Informatics Institute.

The research was published on March 31 in Science Translational Medicine.

Health Informatics Institute Director Jeffrey Krischer, PhD, a professor in the USF Health Morsani College of Medicine’s Department of Internal Medicine, and Hemang M. Parikh, PhD, an assistant professor of bioinformatics in the USF Health Morsani College of Medicine’s Department of Pediatrics, were co-investigators of the study led by the UK researchers at the University of Cambridge.

“Our identification of specific changes in the blood related to natural killer cells provides evidence for the potential involvement of these immune cells in the onset or progression of type 1 diabetes in asymptomatic children,” Dr. Parikh said. “This creates a possible new target for early therapeutic intervention using immune modulation.”

Distinguished University Health Professor Jeffrey Krischer, PhD, director of the USF Health Informatics Institute, leads The Environmental Determinants of Diabetes in the Young (TEDDY) consortium funded by NIH.

Hemang M. Parikh, PhD, assistant professor of bioinformatics at the USF Health Informatics Institute, was a co-investigator for the large-scale, longitudinal study, along with Dr. Krischer.

This study was based on blood samples longitudinally collected from 400 children in The Environmental Determinants of Diabetes in the Young (TEDDY) consortium as they grew older, from birth to age 6. (TEDDY follows children at risk of developing T1D, collecting blood and other samples long before disease symptoms emerge.)

Using genomic approaches and bioinformatics analytical methods, the blood samples were processed to measure the expression of thousands of genes simultaneously. This allowed researchers to identify which genes were switched on and off in each child at varying points in time.

Among the study’s key findings:

• Discovered dynamic, early changes in white blood cell gene expression: Whether or not they progressed to autoimmunity or T1D as they matured, all children in the study showed marked changes in patterns of gene expression in their blood within the first few years of life. This observation highlights the dynamic context in which healthy infants develop early autoimmune disease. When the researchers adjusted for the large changes in gene expression patterns with age, very specific patterns correlating with the rate of progression toward T1D diagnosis became apparent. They identified changes in blood gene expression not seen in healthy children, and these changes began before any other evidence of autoimmunity. Furthermore, the faster the changes occurred, the quicker the children progressed toward T1D onset.

• Linked NK cell signature with T1D progression: By comparing a specific pattern of gene expression associated with T1D progression to groups of genes expressed by many different cell types, the researchers found that this pattern came from a distinct immune cell population known as natural killer (NK) cells. Although NK cells have been observed in the pancreas of children with recent-onset T1D, the role of these immune cells does not figure prominently in current theories explaining how the immunopathology of T1D develops. A more detailed study is needed to determine whether NK cells actively contribute to the T1D-related autoimmune process destroying β-cells in the pancreas, reflecting a pathophysiological response.

• Created a robust predictive model, independently confirmed: The researchers used their new knowledge about longitudinal changes in gene expression patterns to build a model to predict which infants would get T1D and when disease onset was likely to happen. The predictive model incorporates the latest evidence about how the seroconversion of autoantibodies influences progression to T1D. Its accuracy was validated using a second, independent group of prediabetic children from the Type 1 Diabetes Prediction and Prevention Study.

“This type of large-scale research is only possible through the collaboration of many people, including healthy children at risk for T1D, patients with T1D, their families, and countless others,” Dr. Parikh added. “USF is fortunate to play a part in such huge international efforts to tackle this complex autoimmune disease.”

The work was supported by multiple grants from the National Institutes of Health. USF Health’s Dr. Krischer leads the coordinating center for the NIH-funded TEDDY consortium.