Category Archives: Genetic Medicine

Matthew Breen, a professor of genomics at NCState, says his 25-year career has roots in childhood heartbreak.

When I was young, my family had two dogs die from cancer and there was very little we could do to help them, says Breen. There were great strides being made with human cancer research, so why were we unable to help our animal companions more?

We are committed to making that change happen at NCState, he adds.

Today, the internationally recognized researcher specializes in molecular cytogenetics: the study of the structure and function of cells and chromosomes. His work in the College of Veterinary Medicine is helping our pets live longer, healthier lives and unlocking new insights about human cancers along the way.

Since joining NCStates faculty in 2002, Breen has focused on exploring the genetics and genomics of animal diseases, including how they initiate and respond to treatment.

He was a member of the team that sequenced the canine genome 14 years ago. The project sparked a new area of focus in his field: comparing the canine and human genomes to accelerate discoveries for both.

Humans and their furry friends actually share a very similar genetic makeup. And they share certain types of cancers, too. Many cancers diagnosed in humans and dogs have a similar pathology and clinical presentation, says Breen.

But when it comes to canines, its often easier to pinpoint the genetic abnormalities that lead to those cancers. This is especially the case for purebreds. Dogs of the same breed have less genetic variation among them than humans or mixed-breed dogs, making them an ideal genetic model.

Now, Breens lab works extensively in the area and hes become a pioneer in comparative oncology.

By working with human and animal cancers side by side, we are able to find shared features that may help identify the drivers of these cancers and provide opportunities to highlight targets for new therapies, says Breen.

Take, for example, Breens work with the BRAF gene.

Six years ago, his team discovered that a single mutation in the gene was found in 85% of dogs with transitional cell carcinoma (TCC) also called urothelial carcinoma (UC) which is the most common form of bladder cancer in canines. More than 80,000 dogs in the United States will be affected this year alone.

This particular BRAF mutation was already known to exist in some human cancers, but Breens discovery helped unlock its significance for both species. It also revealed an opportunity to create a much-needed tool to aid diagnosis.

By working with human and animal cancers side by side, we are able to find shared features.

In most cases, canine bladder cancer isnt diagnosed until it has reached an advanced stage. Thats because the cancer shares many clinical signs with other, more common urinary tract conditions.

Treatments for the common alternatives may alleviate symptoms temporarily, but they mask the larger problem and buy the cancer more time to progress. In fact, upon diagnosis, more than half of canine bladder cancer cases have already spread.

Identifying the BRAF mutation as a genetic signature of canine bladder cancer was a powerful insight. From there, Breens team began developing a molecular diagnostics test that could identify the mutation and detect the cancer earlier than ever.

That molecular test called CADET BRAF was developed in Breens research laboratory in 2014. Using a urine sample, the system detects cells that possess the BRAF mutation and can monitor changes in the number of mutated cells being shed during treatment of canine TCC and UC.

CADET BRAF represents the worlds first liquid biopsy for the detection of cancer in veterinary medicine, says Breen.

It offers several improvements over current alternatives. Requiring only a simple free-catch urine sample, CADET BRAF is the only non-invasive approach. Other methods often involve costly procedures, such as sedation or anesthesia, that carry additional risks.

The test can also detect bladder cancer in the early stages of the disease, potentially leading to improved outcomes.

CADET BRAF represents the worlds first liquid biopsy for the detection of cancer in veterinary medicine.

We can detect the cancer in dogs that have already presented with clinical signs and avoid repeated attempts to treat solely the signs, says Breen. That allows more time for the veterinarian and owner to develop a plan to treat the root cause. In addition, we have been able to detect the presence of very early disease, several months before the dog has any clinical signs.

Now we have to determine how to manage these preclinical patients, and that is part of ongoing work by our team at NCStates College of Veterinary Medicine, he adds.

The test is also dependable. After rigorous validation of thousands of dogs, Breen says hes found that the presence of the BRAF mutation in canine urine is a highly reliable indicator of the presence of TCC/UC. Weve shown the BRAF mutation isnt found in the urine of healthy dogs or dogs that have other common conditions such as bladder polyps, inflammation or chronic cystitis, he says.

In the two years following the development of CADET BRAF, Breen focused on developing a strong proof of concept. Teaming up with the American Kennel Club, he recruited urine samples from hundreds of dogs to show that the approach could work with real patients.

His next step was commercialization. Breens startup, Sentinel Biomedical, was formed in 2015. Located right on NCStates campus, the company works to develop and scale diagnostic tests for the health care industry.

Since its formation, theyve developed another product called CADET BRAF-PLUS. The test is designed for dogs who dont have the BRAF mutation but do show clinical signs of TCC/UC. It can detect over two-thirds of bladder cancer cases not identified by CADET BRAF, increasing the overall detection sensitivity of the tests to over 95%.

Headquartered right on NCStates campus, Sentinel Biomedical seeks to improve diagnosis and treatment for dogs and their owners.

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Whats next for Sentinel Biomedical? It recently announced a joint venture with Antech Diagnostics, part of MARS. Together theyve formed Antech Molecular Innovations, also based on NCStates Centennial Campus, and work to broaden access to CADET BRAF and CADET BRAF-PLUS.

With the distribution channels of one of the worlds largest animal health providers, we are providing veterinarians with easy access to the tests we develop and enhancing our ability to become a global leader in innovation for veterinary molecular diagnostics, says Breen. And because our work is translational, we also have greater potential to translate our findings to humans.

This will bring the innovations developed at NCState to a whole new level.

Today, the National Cancer Institute spends $6 billion on cancer research annually, and its estimated that less than 0.5% is directed toward veterinary oncology. But Breen sees his innovations and those of his colleagues across the nation as promising steps in the right direction.

Currently, hes involved in a clinical study in the College of Veterinary Medicine that will evaluate the timeline between when a BRAF mutation is detected in a dogs urine and when that dog begins to show clinical signs of TCC/UC. Breen hopes this knowledge will lead to earlier intervention, improved quality of life and increased survival rates.

This will bring the innovations developed at NCState to a whole new level.

Recent collaborations with colleagues at Duke Cancer Institute are also exploring the genetic and environmental factors shared between canine and human bladder cancers. A study proposed by this multidisciplinary team was awarded funding from the V Foundation for Cancer Research in 2019. Such comparative oncology studies, Breen says, have the potential to realize the true value that dogs can bring to our fight against cancer.

Through Antech Molecular Innovations, Sentinel Biomedical has begun pursuing more projects to provide rapid, accessible molecular diagnostics for a variety of cancers that impact our pets and ourselves.

For now, Breen is excited to see his work take on a wider reach. These cancer detection tests will help a new generation of canine companions and their human friends (maybe even kids who are experiencing what Breen did as a child). Whats more, the increased volumes of data theyll collect may unlock insights that lead to the development of new treatment opportunities for cancers in both species.

Although we may not be able to help all dogs with cancer today, we are driven to learn from their cancers to help the dogs of tomorrow, and the families who care for them, says Breen.

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Sniffing Out Cancer in Canines And Humans, Too - NC State News

Delirium is the most common post-surgical complication in older adults. Marked by acute temporary confusion, disorientation and/or agitation, it strikes as many as half of adults over 65 who undergo high-risk procedures such as cardiac surgery and hip replacements.

Postoperative delirium is also tightly linked to Alzheimers disease. Although each can occur independently, Alzheimers is a leading risk factor for delirium, and an episode of delirium puts patients at increased risk for cognitive decline and Alzheimers.

However, the physiological mechanisms that link delirium and Alzheimers disease remain largely unknown.

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Now, in a paper published Nov. 22 in Alzheimers & Dementia: The Journal of the Alzheimers Association, researchers at Harvard Medical School and Beth Israel Deaconess Medical Center shed light on a genetic risk factor for Alzheimers disease that may indirectly influence patients risk of postoperative delirium.

In a study of older adults without dementia undergoing major noncardiac surgery, researchers observed that patients carrying a specific variant of a gene appeared to be much more vulnerable to delirium under certain conditions than people without the variant.

The teams findings could open the door to future interventions to prevent or mitigate postoperative delirium in at-risk patients.

Our findings confirmed our hypothesis that patients risk of postoperative delirium differs by genetic predisposition, said Sarinnapha Vasunilashorn, assistant professor of medicine at HMS and Beth Israel Deaconess and first author of the study. We observed a strong and significant association between high postoperative inflammation and delirium incidence, duration and severity among patients carrying a variant of the gene considered to be risky, while the association was weaker and nonsignificant among noncarriers.

Vasunilashorn and colleagues focused on a gene called APOE, short for apolipoprotein E. The risky version of the gene, notated as APOE 4, is the strongest known genetic risk factor for late-onset Alzheimers disease and a widely studied genetic risk marker for delirium.

While recent studies have shown no direct relationship between APOE 4 and delirium, Vasunilashorns team hypothesized that the gene variant might indirectly influence risk of delirium by modifying the bodys response to inflammationpart of the immune systems natural defense systemindicated by the presence of an inflammatory marker in the blood called C-reactive protein, or CRP.

Using data from the Successful Aging after Elective Surgery (SAGES) study, an ongoing prospective cohort study investigating risk factors and long-term outcomes of delirium, the scientists looked at the incidence, severity and duration of delirium in 560 patients who were at least 70 years old and who underwent major noncardiac surgeries under general or spinal anesthesia. Patients were monitored for delirium, assessed by daily cognitive assessments of attention, memory and orientation throughout their hospital stay.

Analyzing data from patients blood drawn before surgery, immediately after surgery, two days after and one month after revealed that, among carriers of the APOE 4 gene variant, patients with high levels of inflammation had an increased risk of postoperative delirium. However, among noncarriers of the APOE 4 gene variant, the scientists found no such association.

Our findings suggest that APOE 4 may be an indicator of brain vulnerability, said Vasunilashorn. This work may inform the targeting of future interventions, such as anti-inflammatory treatments, for prevention of postoperative delirium and its associated adverse long-term cognitive outcomes in patients with this genetic susceptibility.

Edward Marcantonio, professor of medicine at HMS and Beth Israel Deaconess, is senior author of the study.

This work was supported by the National Institute of Aging of the National Institutes of Health (grants K01AG057836, R03AG061582, P01AG031720, R24AG054259, K07AG041835, R21AG057955, R01AG041274, R21AG048600, R01AG051658 and K24AG035075); the Charles A. King Trust Postdoctoral Research Fellowship Program; Bank of America, N.A., Co-Trustee, and the Alzheimers Association (AARF-18-560786).

Adapted from a Beth Israel Deaconess news release.

Image: kemalbas/Getty Images

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Gene linked to Alzheimers disease plays indirect role in risk for... - ScienceBlog.com

Alzheimers disease is the most common cause of dementia in older adults. Brain changes associated with the disease include abnormal clumps (amyloid- plaques), tangled bundles of fibers (tau tangles), and the eventual death of nerve cells. These changes lead to a progressive decline in memory and thinking skills.

In the search for potential therapies, researchers have been studying known genetic causes of Alzheimers. Some rare forms of Alzheimers can be caused by variations in a single gene. These variants almost always cause symptoms by the time carriers reach middle ageseveral decades earlier than the typical age of onset of the most common form of the disease.

Researchers led by Drs. Yakeel Quiroz from Harvard Medical School and Francisco Lopera from the University of Antioquia have been studying an extended family in Columbia, South America who are affected by one such variant, in a gene calledPSEN1. Of more than 6,000 people in the family, about 1,200 carry the Alzheimers-causingPSEN1mutation.

With the exception of a single woman, all of the family members with thePSEN1mutation have developed symptoms of mild cognitive impairment and Alzheimers dementia in their 40s. This woman didnt develop any symptoms of cognitive decline until her 70s.

The woman volunteered to undergo comprehensive testing, including brain imaging and whole-genome sequencing, to look for possible protective factors. The study was funded in part by NIHs National Institute on Aging (NIA), Office of the Director (OD), and National Institute of Neurological Disorders and Stroke (NINDS). Results were published on November 25, 2019, inNature Medicine.

Brain imaging showed that the woman had high levels of amyloid- plaques in her brain. However, she had low levels of tau tangles. She also had less damage to her brain than would normally be seen in people with Alzheimers.

Whole-genome sequencing revealed that she carried two copies of a rare variation in the geneAPOE, calledAPOE3ch. Different variations ofAPOEhave previously been linked to either protection from or increased risk of Alzheimers disease. In an analysis of 117 other family members, 6% had one copy ofAPOE3ch. But the single copy alone didnt appear to provide protective effects.

The team performed further work to understand how two copies ofAPOE3chmight protect the brain. They found that the variation reduced the ability of the APOE protein to bind a type of sugar found on the surface of brain cells called heparan sulphate proteoglycans (HSPGs). This binding is thought to help tau tangles develop.

The researchers tested whether they could use this knowledge to protect cells that produce normal APOE. They made antibodies that targeted the region where theAPOE3chmutation is. These antibodies reduced the binding of normal APOE to HSPGs to levels seen withAPOE3ch.The findings suggest that therapies to reduce the binding of APOE and HSPG may be a potential way to treat or prevent Alzheimers disease.

Sometimes close analysis of a single case can lead to discovery that could have broad implications for the field, says NIA Director Dr. Richard J. Hodes.

Reference:Arboleda-Velasquez et al. 2019.Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nature Medicine. DOI: 10.1038/s41591-019-0611-3.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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One Womans Genes Could Open Up the Door for Alzheimers Disease Therapies - Technology Networks

Dr Sadaf Farooqi

BRIGHTON, UK The obesity epidemic is not simply the result of changes in the lived environment but a complex interplay between genes and surroundings that has driven people who would have been genetically susceptible but remained thin in previous eras to become obese, says one expert.

This was the argument put forward as part of a debate on whether an individual's body weight is determined by "nature or nurture" at the recent Society for Endocrinology BES Conference 2019 in Brighton, UK.

Before the debate began, Rob Semple, MD, University of Edinburgh, UK, introduced the speakers and polled the audience on their "baseline" views onthe statement: "This house believes that nature not nurture determines our body weight."

The response was 36% "for" the statement (ie, nature) and 64% "against,"which Semple noted suggested that the first speaker, Sadaf Farooqi, MBChB, PhD, "will have her work cut out" to convince the audience that nature is the main driver of obesity.

Farooqui is professor of metabolism and medicine at the University of Cambridge, UK, and was the winner of the 2019 American Diabetes Association Outstanding Scientific Achievement Award.

Farooqi's adversary in the debate was John Wilding, DM, of the University of Liverpool, UK, who Semple described as "similarly formidable."

Farooqi began by saying that the question before the audience is "fundamentally important," and noted that there is plenty of evidence to suggest there is a biological system for regulating body weight.

Experiments have shown that animals and humans maintain a set point for weight that they return to after periods of limited food intake, regardless of how much weight they lose.

Initially, the hypothalamus was found to play a key role in weight regulation, but it was the discovery of leptin that allowed the whole system, with its links to adipose tissue, the pancreas, and the intestines, to be elucidated, she explained.

Work with children then revealed the influence of genetic factors on the body weight "set point."

Identical twins reared apart were found to have a very similar body weight, and adoptive children were shown to have a similar weight to their biologic, rather than adoptive, parents.

Tying these observations to individual or small numbers of genetic variants has, however, proven difficult, beyond the known variants associated with thinness and the rare variants in 15 genes linked to severe obesity.

That is, Farooqi said, until the publication of US research earlier this year testing a polygenic risk predictor involving 2.1 million common variants in more than 300,000 individuals.

The research showed that, across polygenic score deciles, there was a 13-kg gradient in weight and a 25-fold gradient in the risk of severe obesity.

Moreover, another 2019 study, this time by Farooqi's team, revealed some loss of function variants in the melanocortin 4 receptor gene are linked to an increased risk of obesity, type 2 diabetes, and coronary artery disease, and some gain in function variants are linked to a lower risk of obesity and cardiometabolic disorders.

Farooqi believes the reason there is an obesity epidemic is that the physiological system for regulating weight "evolved to stop us starving" but is now faced with "an abundance of food."

The impact of this is all the greater because we live in a "complex food environment," with high sugar and high fat foods that are seen as "very rewarding," as demonstrated on brain scans of people shown pictures of such foods.

Individuals also engage in stress-related eating, which is played out via neural circuits linking the hypothalamus to the limbic system.

She characterized such eating as a "biologically appropriate thing to do because it gives you a rewarding, pleasurable feeling."

She said that, together, this underlines that the "biology of appetite" is a mixture of both innate and learned behaviors.

Farooqi concluded: "I hope I've made the case for you that there is clear, strong, compelling evidence" that weight is regulated by a homeostatic system centered on the hypothalamus, and genetic disorders, tumors, surgery, radiotherapy, and medications can all "perturb" weight regulation.

"In some people, that promotes obesity, in some people it protects them against obesity," she said.

Dr John Wilding

Taking to the podium, Wilding proceeded to present the case for the notion that body weight is determined "by nurture."

He pointed to data from the World Obesity Federation on adult obesity showing that, between the 1960s and 1990s, the prevalence of obesity topped more than 15% in only a few developed countries and no developing nations.

But from 2000 onwards, the situation has completely reversed. At least 15% of the population is obese in most developed countries, rising to over 25% in the United States, Canada, Australia, and the UK, among others. The prevalence of obesity is also rising rapidly in many middle-income countries.

Yet, Wilding pointed out, humanity cannot have evolved genetically to a sufficient extent over that period to account for the change.

He turned to the UK Government's obesity system map, which is a visual representation of the different factors that influence obesity levels.

Although it places physiological energy balance at the heart of the map, and a large part of that is devoted to biologic processes, Wilding highlighted that the visual also places a great degree of emphasis on food production and consumption, societal influences, individual psychology and movement, and the "activity environment."

He also showed data suggesting it is not so much energy and fat intake that is associated with obesity trends as the increase in the number of cars per household and hours spent watching television.

For example, it is estimated that, compared with the 1950s, the average adult now walks, on average, a marathon (approximately 26 miles) less per week, he said.

The Cuban economic crisis of the 1990s also provides an illuminating example, Wilding added.

The sudden end of Soviet subsidies to Cuba led to food shortages, the loss of public and private transport, and the importof 1.5 million bicycles from China.

The subsequent drop in the prevalence of obesity was associated with a reduction in the incidence of diabetes and diabetes-related mortality, with all three increasing substantially once food and transport levels were restored.

Taking a more recent example, Wilding showed longitudinal findings from the HUNT study, which involved almost 119,000 individuals with repeated body mass index (BMI) measurements from 1963, and over 67,000 who were tested for 96 known obesity genes.

The HUNT authors concluded that, although "genetically predisposed people are at greater risk for higher BMI and that genetic predisposition interacts with the obesogenic environment resulting in higher BMI...BMI has increased for both genetically predisposed and nonpredisposed people, implying that the environment remains the main contributor."

Wilding said that, taken together, obesity is "common and increasing almost everywhere," and that the epidemic "is driven by societal change," despite the underlying biology determining an individual's susceptibility.

He ended his pitch to much laughter with a quote by Farooqi from a 2014 review that supports his argument: "Evidence clearly shows that both increases in energy intake and reductions in energy expenditure during physical activity have driven increases in the mean BMI seen in many countries over the past 30years."

Both speakers were then invited back to the podium, allowing Farooqi to respond that, although she did indeed pen that statement in a 2014 review, if one were to look "carefully," the article discussed the last 30 years, and indeed, "our genes haven't changed in that time, but the environment has."

"We agree on that point, and hence my quote," she said, "but what our environment has done is it has unmasked the genetic susceptibility of some individuals, so what we see when we look at the pattern of BMI in the population is that the mean BMI has increased...but also the proportion of people with severe obesity has increased."

She clarified that what this suggests is that, within any population, there are some people who are genetically more susceptible to obesity, so some of those who may not have been obese 30 years ago now are because of the environment.

"It is the environment acting on genetic susceptibility that is contributing to the distribution of BMI," she emphasized.

Wilding again pointed to the HUNT study, which showed that, even in individuals with "thin genes," there has been a rise in mean BMI.

Farooqi said this, in fact, underlines a limitation of that study, which is they only used 96 well-known genetic variants associated with obesity, but the polygenic risk study she highlighted earlier used 2.1 million genetic variants.

Consequently, data from the HUNT study "captures some of the variation but not all," she stressed.

The debate continued, with questions from the floor covering many aspects of obesity.

The final question was directed at Farooqi: "What proportion of somebody's weight is considered to be genetic...as opposed to the nurtured weight?"

She replied this is a "hugely important" question, because "if we don't recognize that theres a biological role for the regulation of weight, how on earth can politicians, with their somewhat different capacity for taking on new information, do that?"

The "evidence suggests around 40% of a person's weight is influenced by genetic factors," she said.

"In some people it's higher, where there are penetrant genes having an effect, in other people it's about 40% with a combination of genes which, added together, influence their risk of either gaining weight or staying thin."

In response, Wilding was keen to stress: "No matter which side of the argument you're on, the point is that this is not the individual's fault."

"It's either a response to their environment...or it's something that they've inherited and don't have individual control over," he noted.

"Sadaf [Farooqi] said it herself, 40% of our body weight is genetic, that means that 60% is environmental, and I rest my case," Wilding said.

However, that did not hold sway with the audience, who, when they voted again at the end of the debate, indicated they had changed their minds: 53% agreed with the statement that nature, not nurture, determines body weight, and 47% disagreed.

A win for the lady, it would seem.

Society for Endocrinology BES 2019. Presented November 11, 2019.

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Nature vs Nurture: What's Fueling the Obesity Epidemic? - Medscape

SAN FRANCISCO, Nov. 21, 2019 /PRNewswire/ -- Invitae Corporation (NYSE: NVTA), a leading medical genetics company, today announced that Shelly Guyer, chief financial officer of Invitae, will participate in a fireside chat at the 31st Annual Piper Jaffray Healthcare Conference on Wednesday, December 4, 2019 at approximately 10:00 a.m. Eastern / 7:00 a.m. Pacific in New York City.

The live, listen-only webcast may be accessed by visiting the investors section of the company's website atir.invitae.com. A replay of the webcast will be available shortly after the conclusion of the fireside chat and will be archived on the company's website.

About Invitae

Invitae Corporation (NYSE: NVTA) is a leading medical genetics company, whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website atinvitae.com.

Source: Invitae Corporation

Contact:Laura D'Angeloir@invitae.com(628) 213-3369

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Invitae to Participate in the 31st Annual Piper Jaffray Healthcare Conference - BioSpace

For patients with cutaneous leishmaniasis, a skin infection transmitted by a sand fly that can lead to painful and disfiguring ulcers, treatment can be grueling. The first-line therapy offered to many requires daily infusions of the metalloid pentavalent antimony for three weeks, and half of patients dont respond to just one round of therapy. Some fail two or even three courses. And the side effects of therapy can range from mere irritation to far more serious conditions.

A new study led by School of Veterinary Medicine researchers with scientists from Brazil has identified biomarkers that predict which patients disease will resolve with antimony, and which patients should be offered an alternative therapy from the outset. Using data from leishmaniasis patients treated in Brazil, the researchers found a number of genes whose expression correlated with treatment outcome. They also discovered that a small difference in parasite numbers made a big difference when it came to the patients response.

They published their findings in the journal Science Translational Medicine.

This study is the result of a progression of studies, each building on one another, that is allowing us to take the step from describing the biology of this disease to identifying which patients might need alternative treatments, says Phillip Scott, vice dean of Penn Vet and a co-senior author on the work.

Were moving into the realm of figuring out how to translate this to patients, adds Daniel P. Beiting, co-senior author on the paper and an assistant professor at Penn Vet. If we can quickly and noninvasively monitor the targets we found, it could be important not only for leishmaniasis but potentially also for other skin diseases, like chronic wounds or psoriasisanything where these genes are playing a role.

Scott has been working on leishmaniasis and performing research in Brazil for three decades, identifying the factors that contribute to the diseases pathology. Over the last several years, hes collaborated with Beiting to employ genomic techniques to characterize more features of the disease and to identify potential targets for therapy.

In 2017, the Penn Vet-led team found that chronic disease can arise when the immune systems response to the Leishmania parasite goes awry, leading to persistent inflammation. The findings implicated a type of immune cell known as CD8 T cells. Yet their findings still didnt explain why so many patients fail to respond to the antiparasitic drug antimony.

To answer this question, they used a more open-ended approach to finding patterns in their data, a pretreatment collection of skin biopsies from 21 people with leishmaniasis and seven people without the disease who served as controls.

The challenge of human studies is that there are so many confounding variables, says Beiting. If you say, Im going to compare people who have responded to those who didnt respond, it sometimes doesnt work because in those two groups there are a lot of other variables at play: sex, age, other comorbidities. So, what we did instead was say, If we believe these patients are variable in the way they respond to treatment, why dont we look at what genes are variable?

Narrowing down the many genes they identified in this analysis to focus on the top 250 most variable among patients, they found a subset that correlated with treatment failure. Looking at a second set of data from different patients, they were able to confirm that eight of these genes were able to predict treatment failure in both groups.

And lo and behold, included in that group were some of the genes that we already knew were key players from previous studies in humans and mice, says Beiting, including elements of the CD8 signaling pathway the group had uncovered in 2017.

We also found genes that we hadnt expected but fit into the broad theme of this cytolytic, inflammatory pathway, says Scott.

In previous studies, researchers had notedand been somewhat puzzled bythe fact that skin lesions contained few parasites. The current studied confirmed this, using genetic sequencing methods to identify the presence and quantity of parasites in the patient samples. But their quantitative methods also revealed that, while numbers were low across the board, how low they were mattered.

Very few versus very, very few apparently makes a difference, says Scott. Theres a small but significant cutoff between failure and cure.

As the group gets closer to moving their findings to the clinic, some hurdles remain. They have zeroed in on a few biomarkers, notably the signaling molecule IL-1 and a protein complex known as NLRP3, as ones that could be used in a diagnostic setting to make informed predictions about patient treatment outcomes.

Theyre also working to see whether a less invasive method than a biopsy could give reliable data about a patients disease.

Were laying the foundation for being able to take samples on site and assess them on site, says Beiting, potentially using portable diagnostic devices that could be practical for use in remote clinics like the one the team has collaborated with in Brazil.

And theyre continuing to work in the lab to further study the genes that appear to be important in driving disease.

This latest work, tying in the outcome of treatment, emphasizes how important it would be to block these pathways, Scott says.

Phillip Scott is vice dean for research and academic resources and a professor of microbiology and immunology in the Department of Pathobiology in the University of Pennsylvania School of Veterinary Medicine.

Daniel P. Beiting is an assistant professor in the Department of Pathobiology in the University of Pennsylvania School of Veterinary Medicine.

Scott and Beiting coauthored the study with researchers from Penn Vet, including lead author Camila Farias Amorim, Fernanda O. Novais, Ba Nguyen, and Ana M. Misic, as well as Lucas P. Carvalho and Edgar M. Carvalho of Universidade Federal da Bahia in Brazil.

The study was supported by the National Institutes of Health (grants AI088650 and AI030639) and Penn Vets Center for Host-Microbial Interactions.

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Predicting treatment outcome for leishmaniasis - Penn: Office of University Communications