A new blindness gene uncovered in a canine study

A new blindness gene uncovered in a canine study

Inherited retinal dystrophy is a common cause of blindness, with as many as two million people suffering from the disorder globally. No effective treatment is available for retinal dystrophies. Gene therapy is expected to offer a solution, but developing such therapies is possible only when the genetic cause of the disease is known. Related mutations have been identified in more than 70 genes so far, but the genetic background of the disease remains unknown in as many as half of the patients.

“Retinal dystrophy has been described in over 100 dog breeds, with related investigations helping to identify new genes associated and pathogenic mechanisms with blindness across different breeds. IFT122 is a good example, offering a potential explanation for unsolved human cases as well,” Professor Hannes Lohi states.

Data encompassing more than a thousand Lapponian Herders and Finnish Lapphunds from a canine DNA bank were utilized in the study. Previously, several retinal dystrophy genes have been described in both breeds.

“Among other finds, two eye disease genes have previously been identified in Lapponian Herders, but they have not accounted for all cases. In some dogs, the disease is caused by the IFT122 gene. The finding is significant since gene tests can now distinguish between retinal dystrophies associated with different genes in breeds, which makes a difference in monitoring disease progression, making prognoses, and developing novel treatments. Diagnostics are getting better and making the job of veterinarians easier,” explains Maria Kaukonen, Doctor of Veterinary Medicine.

The gene discovery also facilitates the understanding of retinal biology. IFT122 is part of a protein complex linked with ciliary function in the retina.

“The age of onset varies, and the disease progresses slowly in some dogs. IFT122 is known to contribute to the transport of opsin in photoreceptor cells. The gene variant disturbs this transport and results in progressive blinding. Since IFT122 is associated with cilia’s function, which is important to the body, we studied some of the dogs even more closely with regard to other issues potentially linked with cilia-related disturbances, such as renal abnormalities or serious developmental disorders of the internal organs. We found that the damage seems to be limited to the retina alone. This information helps us understand the gene’s mechanisms of action,” Kaukonen adds.

The findings are also significant for further plans to remove the disease from different breeds. In the Lapponian Herders and Finnish Lapphunds, the share of individuals carrying the gene variant was 28% and 12%, respectively.

“This is a recessively inherited disease, which means that a dog that will become blind inherits the variant from both parents, who are both carriers of the variant. Gene testing can help avoid carrier-carrier combinations, easily preventing the birth of sick dogs. A new concrete tool has been developed based on the study for the benefit of breeders,” says Lohi.

The new study is part of a broader research project on the genetic background of inherited diseases by Professor Lohi’s research group. Kaukonen recently transferred to a research group active at the University of Oxford, focusing on developing gene therapies for retinal dystrophy. At the same time, Kaukonen and Lohi are continuing close collaboration to survey a range of eye diseases together with the Helsinki University Hospital and other operators.

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Will we need COVID-19 booster shots? Study considers more vaccinations

vaccine

As people across Maryland and the country seek their first dose of COVID-19 vaccine, Jean Armstrong got her third.

The Baltimore County public school administrator was one of the first people to get a pair of shots of the Pfizer/BioNTech vaccine last May as studies began to test its safety and efficacy. She returned this week to the University of Maryland in Baltimore to help researchers understand whether a booster could continue to keep her from getting seriously sick from the coronavirus.

“I’m a believer in vaccines and think they work, and it’s important to be involved,” Armstrong said of her willingness to be vaccinated again. “It seems like realistically we have to be prepared for boosters and vaccines for variants.”

Researchers and vaccine manufacturers are actively preparing for the possibility that people will need to get another vaccination or regular ones to keep at bay the current coronavirus or a mutated and more nefarious version.

The vaccines now approved for use are considered highly effective at staving off infection, particularly severe infection, but no one knows how long immunity lasts. It’s widely believed that it wanes at least somewhat over time.

And data is beginning to show that the vaccines are at least somewhat less potent against emerging variants. There are several now widely circulating, including ones discovered first in South Africa, Brazil and the United Kingdom. Others with potentially concerning mutations have been logged in the United States in California and most recently in New York.

The research seeks to answer some questions and “grease the wheels” for others, said Dr. Kirsten E. Lyke, who is helping oversee the study at the University of Maryland School of Medicine’s Center for Vaccine Development and Global Health.

Specifically, Lyke, director of the Malaria Vaccine and Challenge Unit, said researchers will look at immunity before and after a booster, which is a regular dose of the Pfizer vaccine. They also will assess how well people tolerate another shot.

Twenty-four hours after her third shot, Armstrong, a Harford County woman in her 40s, said she’s not had side effects except a bit of arm soreness. She had more flu-like symptoms from the first two shots she received last May.

Federal regulators gave the Pfizer vaccine authorization for emergency use in December after a remarkably speedy development period of just months rather than years. It continues to be evaluated for full approvals.

A similar vaccine from Moderna also has been authorized and a third from Johnson & Johnson is expected to get the go-ahead for use within days.

All are considered highly effective against severe disease. Researchers say, however, that the public may need another shot eventually. People may even need to have annual shots, as they do for the flu.

The vaccine makers are preparing for that possibility now, as well as moving quickly to adapt the vaccines for variants.

The U.S. Food and Drug Administration offered guidance this week to assure the public that the adapted vaccines will be tested, but the process won’t be delayed. The vaccine makers will be permitted to do small-scale studies of maybe a few hundred people to test the upgrades, rather than repeat large studies with tens of thousands of people for each vaccine.

“We know the country is eager to return to a new normal and the emergence of the virus variants raises new concerns about the performance of these products,” said Dr. Janet Woodcock, acting FDA commissioner, in a statement. “By issuing these guidances, we want the American public to know that we are using every tool in our toolbox to fight this pandemic, including pivoting as the virus adapts.”

Pfizer and Moderna both said this week that work is underway.

Pfizer said Thursday that it was studying a third dose in its initial phase 1 participants, who include Armstrong, to evaluate the safety and tolerability of a booster shot of the existing vaccine. The vaccine was initially tested at four sites, including Maryland.

That study also will inform efforts to adapt the vaccine to address emerging variants, said officials with the New York-based pharmaceutical giant.

“While we have not seen any evidence that the circulating variants result in a loss of protection provided by our vaccine, we are taking multiple steps to act decisively and be ready in case a strain becomes resistant to the protection afforded by the vaccine,” said Albert Bourla, Pfizer chairman and CEO, in a statement.

“This booster study is critical to understanding the safety of a third dose and immunity against circulating strains,” he said.

Moderna is following a similar path, and its officials said this week that the Massachusetts drugmaker already had sent a vaccine adapted for the variant found in South Africa to the National Institutes of Health for study.

The officials said the company would update its vaccine as many times as necessary.

“As we seek to defeat COVID-19, we must be vigilant and proactive as new variants of SARS-CoV-2 emerge,” said Stéphane Bancel, Moderna CEO, in a statement. “Leveraging the flexibility of our mRNA platform, we are moving quickly to test updates to the vaccines that address emerging variants of the virus in the clinic.”

At the University of Maryland, the first few people out of the hundreds who initially participated in the phase 1 trial got their third dose this week

All of those participants are being followed for more than two years as part of the FDA’s final approval process for the vaccine. Armstrong said she was surprised to be called back already for another shot, but wanted to help researchers as the pandemic evolved.

Despite her discomfort with needles, she had agreed to participate in another study years before, one that produced a vaccine for the H1N1 flu outbreak in 2009. She volunteered again last year.

Scientists don’t know why some people have more adverse reactions than others. The previous COVID-19 shots had given Armstrong chills, body aches and a fever, which are typical and normally short-lived responses.

“I was pleasantly surprised this time,” she said. “It’s 24 hours later and my arm hurts just a little bit. It’s been easy so far.”

Lyke said that as researchers were searching initially for the right vaccine makeup and dose, participants were given any of four versions of the Pfizer vaccine in three different amounts. Others were given a placebo, but they have since been fully vaccinated.

She said all the versions induced an immune response in people, but by June researchers had narrowed the vaccine and dose to the most effective and best-tolerated one.

Messenger RNA vaccines had long been studied for infectious diseases and even cancer, but the technology had never been approved for use. Instead of weakened or dead virus, mRNA vaccines deploy a bit of the virus’ genetic code to instruct cells to produce more of the viral protein, which in turn induces an immune response. The resulting antibodies fight the virus when they later come into contact with it.

All participants getting a booster shot at Maryland are at least six months past their second vaccination. Researchers took blood before and after the latest shots to determine the effects.

“If the immune response waned we’d know they needed a booster,” Lyke said. “And we wanted to see how they would respond to a booster, meaning they tolerated it and had another good immune response.”

She said it’s unknown whether anyone will need a booster, will need seasonal boosters or will need adapted shots for variants.

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Michigan woman dies from COVID-19 after lung transplant: study

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A Michigan woman contracted COVID-19 and died last fall after she got a double-lung transplant from a donor who turned out to have the virus, according to a study.

The incident may be the first proven case in the U.S. in which the coronavirus was transmitted through an organ transplant, researchers say in a report published by the American Journal of Transplantation.

“We would absolutely not have used the lungs if we’d had a positive COVID test,” Dr. Daniel Kaul, director of the Transplant Infectious Disease Service at the University of Michigan Medical School and one of the co-authors of the study, told Kaiser Health News.

All the screening that we normally do and are able to do, we did,” Kaul added. The donor was a woman from the Upper Midwest who died after suffering from a severe brain injury in a car accident.

The recipient had chronic obstructive lung disease and was operated on at University Hospital in Ann Arbor.

Nose and throat samples collected from the donor and the recipient had tested negative for COVID-19.

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However, three days after the surgery, the woman developed a high fever, low blood pressure, heavy breathing and a lung infection, according to researchers.

Doctors decided to test for COVID-19 after the woman went into septic shock. Fluids taken from the lungs were also tested and the results were positive.

“History obtained from [the donor’s] family revealed no history of travel or any recent fever, cough, headache, or diarrhea,” the study says.

“It is unknown if the donor had any recent exposures to persons known or suspected to be infected with SARS-CoV-2.”

Four days after the operation, a surgeon who had handled the donor’s lungs also tested positive for the bug, but later recovered.

Meanwhile, the transplant recipient deteriorated quickly. She died 61 days after the surgery.

Kaul concluded that the Michigan case proves there needs to be more extensive sampling of organs before transplant surgery, especially in regions where there are more cases of COVID-19.

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Deaths from food allergy rare and decreasing in the UK, finds study

food allergy

Deaths from serious allergic reactions (“anaphylaxis”) due to food have declined over the past 20 years, an analysis of UK NHS data had found. This is despite an increase in hospital admissions for food-induced anaphylaxis over the same time.

The analysis, conducted by scientists from Imperial College London and published in the BMJ also found that cows’ milk is the commonest single cause of fatal food-induced allergic reactions in school-aged children.

Around two million people are thought to live with a food allergy in the UK. Symptoms of an allergic reaction include an itching sensation inside the mouth, ears and throat, an itchy rash, and swelling of the face. In anaphylaxis, which can sometimes be fatal, a person can develop breathing difficulties, trouble swallowing or speaking. However, deaths from anaphylaxis are rare. It is estimated there are less than 10 fatalities due to food allergy per year in the UK.

Dr. Paul Turner, lead author of the study from Imperial’s National Lung and Heart Institute said: “This study raises two important points. The first is that despite hospital admissions increasing, the number of deaths from food-induced anaphylaxis has fallen. However, the second, more worrying point, is that cow’s milk is now the single most common cause of fatal allergic reactions in children. There is now a lot of awareness of allergies to peanut and tree nut, but many people think milk allergy is mild, perhaps because most children outgrow it. However, for those who don’t, it remains a big problem because milk is so common in our diet, and people don’t realise how dangerous it can be.”

The study, funded by the Food Standards Agency and Medical Research Council, analysed UK hospital admissions for food-induced anaphylaxis between 1998-2018, and how these compare to fatal anaphylaxis events.

Food Standard Agency ‘s Head of Policy and Strategy for Food Hypersensitivity, Sushma Acharya, said: “These important findings help us understand the trends of severe food induced allergic reactions, like who is most at risk and which foods are responsible. This research is part of a wider study we have commissioned to support our ambition for the UK to be the best place in the world to be a food hypersensitive consumer. We want to improve the quality of life for people living with food hypersensitivity and support them to make safe informed food choices.

“We note that young adults are most at-risk from severe and fatal allergic reactions to foods. Our upcoming promotion to encourage young people to ask for allergen information when ordering food is one example of how this valuable data will be used to inform our campaigns and policy making.”

The team at Imperial are now investigating why some people may be more susceptible to severe allergic reactions, and whether factors such as genetics may play a role.

During the study period from 1998 to 2018, hospital admissions for food-induced anaphylaxis increased by 5.7% per year, or three-fold (from 1.23 to 4.04 admissions per 100,000 population per year).

Over the same time, the case fatality rate (number of fatalities compared to hospital admissions) for food-anaphylaxis more than halved, from 0.7% in 1998 to 0.3% in 2018. This may be due to better awareness of food allergy, and how to quickly recognise and treat serious allergic reactions.

Deaths from food-induced anaphylaxis are rare. The study also assessed food-related anaphylaxis fatalities, recorded since 1992, when data first became available. There had been 187 fatalities since 1992 where the cause of death was likely to be food-induced anaphylaxis. At least 86 (46%) of these were due to peanuts or tree nuts such as almonds, cashews and walnuts.

Sixty-six deaths were reported in children, of which 14% were caused by peanuts, 9% by tree nuts and in 12% of cases, the nut could not be identified. However, the most common single cause of fatal anaphylaxis was cows’ milk, responsible for 26% of cases. Furthermore, there was a trend towards a greater proportion of reactions being caused by milk since 1992.

The research team add that cow’s milk is quite protein-rich, meaning a small amount of cow’s milk can result in a significant exposure.

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Study explores neurocognitive basis of bias against people who look different

face

The “scarred villain” is one of the oldest tropes in film and literature, from Scar in “The Lion King” to Star Wars’ Darth Vader and the Joker in “The Dark Knight.” The trope is likely rooted in a long-evolved human bias against facial anomalies—atypical features such as growths, swelling, facial paralysis, and scars. A new brain-and-behavior study from researchers in the Perelman School of Medicine at the University of Pennsylvania illuminates this bias on multiple levels.

The researchers, whose findings were published this week in the Annals of the New York Academy of Sciences, used surveys, social simulations, and functional MRI (fMRI) studies to study hundreds of participants’ responses and attitudes towards attractive, average, and anomalous faces. The findings clarify how the ‘anomalous-is-bad’ stereotype manifests, and implicate a brain region called the amygdala as one of the likely mediators of this stereotype.

“Understanding the psychology of the ‘anomalous-is-bad’ stereotype can help, for example, in the design of interventions to educate the public about the social burdens shouldered by people who look different,” said lead author Clifford Workman, Ph.D., a postdoctoral researcher in the Penn Center for Neuroaesthetics. The center is led by Anjan Chatterjee, MD, a professor of Neurology at Penn Medicine, who was senior author of the study.

Bias against people with facial disfigurements has been demonstrated in various prior studies. Researchers broadly assume that this bias reflects ancient adaptive traits which evolved to promote healthy mate selection, for example, and to steer us clear of people who have potentially communicable diseases. Regardless the cause, for many people, their facial anomalies render them unjust targets of discrimination.

In their study, Workman and colleagues investigated how this bias manifests at different levels, from expressed attitudes towards faces, to actual behavior during simulated social interactions, and even down to brain responses when viewing faces.

In one part of the study, the researchers showed a set of faces that were either average-looking, attractive, or anomalous to 403 participants from an online panel, and asked them to rate the depicted people on various measures. The researchers found that, compared to more attractive faces, participants considered anomalous faces less trustworthy, less content, and more anxious, on average. The anomalous faces also made the participants feel less happy. Participants also acknowledged harboring “explicit bias” reflected in negative expectations about people with anomalous faces as a group.

In the other part of the study, Workman and colleagues examined moral attitudes and dispositions, the behavior during simulated social interaction, and fMRI-measured brain responses, for 27 participants who viewed similar sets of faces.

Here again there was some evidence of the anomalous-is-bad habit of thinking, though it was not clear that this translated into mistreatment of people with anomalous faces. For example, in a simulated donation game measuring pro-sociality—the willingness to be positive and helpful towards another—the participants were not significantly less pro-social towards anomalous-looking people. However, participants in the highest tier of socioeconomic status, compared to the others, were significantly less pro-social towards anomalous-looking people.

On fMRI scans, brain regions called the amygdala and the fusiform gyri showed significant neural responses specifically to anomalous faces. Activity in a portion of the left amygdala, which correlated with less pro-sociality towards anomalous faces, also seemed related to participants’ beliefs about justice in the world and their degree of empathic concern.

“We hypothesize that the left amygdala integrates face perception with moral emotions and social values to guide behavior, such that weaker emotional empathy, and a stronger belief that the world is just, both facilitate dehumanizing people with facial anomalies,” Chatterjee said.

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Covid new symptoms: New study shows emerging new symptoms for Coronavirus

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There are a plethora of symptoms associated with COVID-19 and the list continues to be updated. A new study suggests chills, loss of appetite, headache and muscle aches should be added to the list. The findings are based on swab tests and questionnaires taken from June up until last month as part of Imperial College London’s REACT study of over one million people.

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Study shows safety of adaptive radiotherapy in non small cell lung cancer patients

lung

The NRG Oncology and the American College of Radiology Network (ACRIN) multicenter, phase II trial, NRG-RTOG 1106/ACRIN 6697, is the first randomized trial to demonstrate the feasibility and safety of performing adaptive radiotherapy (RT) escalation in patients with locally advanced non-small cell lung cancer (NSCLC). The improvement of in-field tumor control appeared similar to the level (1% improvement with 1Gy dose escalation) of the single institutional study of adaptive radiotherapy performed at University of Michigan, and different from that of RTOG617 with non-adaptive high dose radiation in stage III NSCLC. The results were presented at the virtual edition of the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer, Singapore.

The NRG Oncology randomized phase III trial NRG-RTOG 0617 offered the insight that a higher dose of radiotherapy delivered with chemoradiotherapy actually worsened tumor control and survival for this patient population. NRG-RTOG 1106/ACRIN 6697 was designed to bridge this treatment gap by testing adaptive radiotherapy dose escalation with chemotherapy to see if this treatment could enhance two-year local-regional tumor control compared to the 60 Gy standard dose of radiotherapy this patient population typically receives. The use of fluorodeoxyglucose-positron emission tomography (FDG-PET/CT) imaging would help identify resistant aggressive tumor identified mid-treatment and adapt personalized treatment plans per each individual’s tolerance.

Patients with Stage III NSCLC were randomly assigned in a 2:1 ratio to receive either the standard radiotherapy at 60 Gy (Standard Arm) or the adaptive radiotherapy treatment that resulted in a median dose escalation of 11 Gy (Adaptive Arm). Patients on both treatment arms received FDG-PET/CT imaging at mid-treatment for radiation. The Standard Arm included 43 eligible patients whereas the Adaptive Arm included 84 eligible patients. The Standard Arm had a median follow up of 3.7 years for surviving patients with acceptable overall radiotherapy compliance rates (92.9% and 50% per protocol). The 2-year overall local-regional progression free rate was 59.5% (95% CI: 37.9, 75.7). Median local-regional progression free time was 27.5 months (95% CI: 14.3, not reached) in the Standard Arm. The Adaptive Arm had a median follow up of 3.4 years for surviving patients with acceptable overall radiotherapy compliance rates (95.8% for the initial course of treatment and 32.4% for adaptive course per protocol) and 2-year overall local-regional progression free rates were 54.6% (95% CI: 39.9, 67.0). Median local-regional progression free time was 28.4 months (95% CI: 19.1, not reached) in the Adaptive Arm. There were no significant differences in grade 3 or worse toxicity of lung, esophagus, and heart or overall survival, progression-free survival, and lung cancer specific survival between treatment arms. Adaptive radiotherapy did increase in-field local-regional tumor control by 11% and in-field primary tumor control by 17% during the trial.

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WHO issues new clinical advice for coronavirus patients, plans to study 'long COVID'

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Nearly a year after the World Health Organization (WHO) first declared the novel coronavirus a public health emergency, the agency has issued new clinical advice for both at-home and hospitalized treatment of COVID-19 patients.

The agency also announced forthcoming plans to study so-called “long-COVID” or otherwise called “COVID long-haulers” who continue to suffer from symptoms well after the infection is gone.

The agency also revealed plans to study long-COVID.
(iStock)

“Understanding this condition is one of WHO’s priority areas of work,” the agency said, in a news release posted Tuesday. “In February 2021, WHO will organize a series of consultations to reach consensus on a description of this condition and its subtypes, and case definitions. The scientific understanding will inform the name of the condition. The consultations will include a broad range of stakeholders, including patient groups.”

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Meanwhile, for current patients who do not require hospitalization, WHO is recommending using pulse oximetry to measure oxygen levels in the blood. The over-the-counter products should be “coordinated with other aspects of home care, such as education for the patent and care provider and regular follow-up of the patient.”

For those who require hospitalization, the agency suggests health care providers consider using low-dose anticoagulants to prevent blood clots, as well as placing patients who receive non-invasive supplemental oxygen on their stomachs to increase oxygen flow.

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The agency noted the guidelines are “a living document, updated regularly as more data becomes available.” The update comes on the same day WHO announced it was working with Moderna to accelerate approval for its COVID-19 shot for emergency use listing.  

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Study suggests drug intervention may prevent doxorubicin-induced cardiac injury

chemotherapy

There could be an intervention on the horizon to help prevent heart damage caused by the common chemotherapy drug doxorubicin, new research suggests.

Scientists found that this chemo drug, used to treat many types of solid tumors and blood cancers, is able to enter heart cells by hitchhiking on a specific type of protein that functions as a transporter to move a drug from the blood into heart cells.

By introducing another anti-cancer drug in advance of the chemo, the researchers were able to block the transporter protein, effectively stopping the delivery of doxorubicin to those cardiac cells. This added drug, nilotinib, has been previously found to inhibit activation of other, related transport proteins.

The current findings are based on lab experiments in cell cultures and mice. The researchers are continuing studies with hopes to start designing human trials of the drug intervention later in 2021.

“The proposed intervention strategy that we’d like to use in the clinic would be giving nilotinib before a chemotherapy treatment to restrict doxorubicin from accessing the heart,” said first author Kevin Huang, who graduated in December from The Ohio State University with a Ph.D. in pharmaceutical sciences. “We have pretty solid preclinical evidence that this intervention strategy might work.”

The study is published today in Proceedings of the National Academy of Sciences.

Doxorubicin has long been known for its potential to increase patients’ risk for serious heart problems, with symptoms sometimes surfacing decades after chemo, but the mechanisms have been a mystery. The risk is dose-dependent—the more doses a patient receives, the higher the risk for cardiac dysfunction later in life that includes arrhythmia and a reduction in blood pumped with each contraction, a hallmark symptom of congestive heart failure.

Huang worked in the lab of senior study authors Shuiying Hu and Alex Sparreboom, faculty members in pharmaceutics and pharmacology and members of the Ohio State Comprehensive Cancer Center’s Translational Therapeutics program. This research and other studies targeting different transport proteins to prevent chemo-related nerve pain were also part of Huang’s dissertation.

“Our lab works on the belief that drugs don’t naturally or spontaneously diffuse into any cell they would like to. We hypothesize that there are specialized protein channels found on specific cells that will facilitate movement of internal or external compounds into the cell,” Huang said.

For this work, the team focused on cardiomyocytes, cells composing the muscle behind the heart contractions that pump blood to the rest of the body. The researchers examined cardiomyocytes that were reprogrammed from skin cells donated by two groups of cancer patients who had been treated with doxorubicin—some who suffered cardiac dysfunction after chemo, and others who did not.

The scientists found that the gene responsible for production of the transport protein in question, called OCT3, was highly expressed in the cells derived from cancer patients who had experienced heart problems after treatment with doxorubicin.

“We used mouse models and engineered cell models to demonstrate doxorubicin does transport through this protein channel, OCT3,” Huang said. “We then looked prospectively into what this means from a therapy perspective.”

Blocking OCT3 became the goal once researchers found that genetically modified mice lacking the OCT3 gene were protected from heart damage after receiving doxorubicin. Further studies showed that inhibiting OCT3 did not interfere with doxorubicin’s effectiveness against cancer.

Hu and Sparreboom have specialized in a class of drugs called tyrosine kinase inhibitors, which block specific enzymes related to many cell functions. Nilotinib, a chronic myeloid leukemia drug, is a tyrosine kinase inhibitor that is also known to act on OCT3.

Additional experiments showed that cardiac function was preserved in mice that were pretreated with nilotinib before receiving doxorubicin—and the pretreatment did not interfere with doxorubicin’s ability to kill cancer cells.

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Study finds genetic clues to pneumonia risk and COVID-19 disparities

pneumonia

Researchers at Vanderbilt University Medical Center and colleagues have identified genetic factors that increase the risk for developing pneumonia and its severe, life-threatening consequences.

Their findings, published recently in the American Journal of Human Genetics, may aid efforts to identify patients with COVID-19 at greatest risk for pneumonia, and enable earlier interventions to prevent severe illness and death.

Despite the increasing availability of COVID-19 vaccines, it will take months to inoculate enough people to bring the pandemic under control, experts predict. In the meantime, thousands of Americans are hospitalized and die from COVID-19 each day.

“This study is so important because we performed analyses separately in participants of Caucasian ancestry as well as African ancestry to identify genetic risk factors contributing to pneumonia susceptibility and severity,” said Jennifer “Piper” Below, Ph.D., associate professor of Medicine and the paper’s corresponding author.

“Combined with systemic racism and socioeconomic factors that have been reported by others, these genetic risk differences may contribute to some of the disparities we observe in COVID-19 outcomes,” Below said.

The researchers conducted genome-wide association studies (GWAS) of more than 85,000 patients whose genetic information is stored in VUMC’s BioVU biobank and which has been linked to “de-identified” electronic health records stripped of personal identifying information. GWAS can identify associations between genetic variations and disease.

With colleagues from the University of North Carolina at Chapel Hill, the University of Texas MD Anderson Cancer Center in Houston, and the Icahn School of Medicine at Mount Sinai in New York, the VUMC researchers identified nearly 9,000 cases of pneumonia in patients of European ancestry, and 1,710 cases in patients of African ancestry.

The strongest pneumonia association in patients of European ancestry was the gene that causes cystic fibrosis (CF). This disease produces abnormally thick mucus leading to chronic infections and progressive respiratory failure.

In patients of African ancestry, the strongest pneumonia association was the mutation that causes sickle cell disease (SCD), a red blood cell disorder that increases the risk for pneumonia, influenza and acute respiratory infections.

Children with CF and SCD are at particular risk for severe disease if they contract COVID-19.

The researchers found that “carriers” who are unaffected by CF yet carry a copy of the CF gene had a heightened susceptibility to pneumonia, and those who are unaffected by SCD yet carry a copy of the SCD mutation were at increased risk for severe pneumonia.

Further studies will be needed to determine whether these carriers also bear “a silent, heightened risk for poor outcomes from COVID-19,” the researchers said.

To identify other genetic variations that increase pneumonia risk, they removed patients with CF and SCD from their analysis, repeated the GWAS, and used another technique called PrediXcan, which correlates gene expression data with traits and diseases in the electronic health record.

This time they found a pneumonia-associated variation in a gene called R3HCC1L in patients of European ancestry, and one near a gene called UQCRFS1 in patients of African ancestry. The molecular function of R3HCC1L is unclear, but deletion of the UQCRFS1 in mice disrupts part of their infection-fighting immune response.

“Although our understanding about the genetic mechanism of pneumonia is still limited, this study identified the novel candidate genes, R3HCC1L and UQCRFS1, and offered an insight for further host genetic studies of COVID-19,” said the paper’s first author, Hung-Hsin Chen, Ph.D., MS, a postdoctoral fellow in Below’s lab.

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