Nox-ious link to cancer Warburg effect

Invitation from a talk by San Martin recently gave in Read more

Viral vectors ready for delivery

The phrase “viral vector” sounds ominous, like something from a movie about spies and Internet intrigue. It refers to a practical delivery system for the gene of your Read more

Exotic immune systems are big business

Research on lampreys’ variable lymphocyte receptors may seem impractical. Good examples exist of weird animals' immune systems becoming big Read more

Heart

Aging, CVD risk factors and progenitor cells

Cardiologists Ibhar Al Mheid, Arshed Quyyumi and colleagues from Emory’s Clinical Cardiovascular Research Institute recently published a paper that weaves together insights from past research on circulating progenitor cells. They tease apart the influences of age and cardiovascular disease (CVD) risk factors on these cells, whose regenerative capacity has made them the target of much investigation. From this research, one can infer that the circulatory system has a limited regenerative capacity, and stress upon the system earlier in life depletes it later.

Circulating progenitor cells are rare cells in the blood that can become white or red blood cells, as well as endothelial cells, which line blood vessels and repair them when damaged by cardiovascular disease. Quyyumi and his colleagues have sought to deliver progenitor cells, derived from the patient’s own bone marrow, to the heart – or less invasively, spur them out of the bone marrow with drugs. Read more

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Stay out, stray stem cells

Despite the hubbub about pluripotent stem cells’ potential applications, when it comes time to introduce products into patients, the stem cells are actually impurities that need to be removed.

That’s because this type of stem cell is capable of becoming teratomas – tumors — when transplanted. For quality control, researchers want to figure out how to ensure that the stem-cell-derived cardiac muscle or neural progenitor or pancreas cells (or whatever) are as pure as possible. Put simply, they want the end product, not the source cells.

Stem cell expert Chunhui Xu (also featured in our post last week about microgravity) has teamed up with biomedical engineers Ximei Qian and Shuming Nie to develop an extremely sensitive technique for detecting stray stem cells.PowerPoint Presentation

The technique, described in Biomaterials, uses gold nanoparticles and Raman scattering, a technology previously developed by Qian and Nie for cancer cell detection (2007 Nature Biotech paper, 2011 Cancer Research paper on circulating tumor cells). In this case, the gold nanoparticles are conjugated with antibodies against SSEA-5 or TRA-1-60, proteins that are found on the surfaces of stem cells. Read more

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Microgravity means more cardiac muscle cells

Cardiac muscle cells derived from stem cells could eventually be used to treat heart diseases in children or adults, reshaping hearts with congenital defects or repairing damaged tissue.

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Cardiomyocytes produced with the help of simulated microgravity. Red represents the cardiac muscle marker troponin, and green is cadherin, which helps cells stick to each other. Blue = cell nuclei. From Jha et al SciRep (2016).

Using the right growth factors and conditions, it is possible to direct pluripotent stem cells into becoming cardiac muscle cells, which form spheres that beat spontaneously. Researchers led by Chunhui Xu, PhD, director of the Cardiomyocyte Stem Cell Laboratory in Emory’s Department of Pediatrics, are figuring out how to grow lots of these muscle cells and keep them healthy and adaptable.

As part of this effort, Xu and her team discovered that growing stem cells under “simulated microgravity” for a few days stimulates the production of cardiac muscle cells, several times more effectively than regular conditions. The results were published on Friday, Aug. 5 in Scientific Reports. The first author of the paper is postdoctoral fellow Rajneesh Jha, PhD. Read more

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Focal adhesions in Technicolor

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Mouse embryonic fibroblasts forming focal adhesions

Congratulations to Alejandra Valdivia, PhD, winner of the Best Image contest held as part of the Emory Postdoctoral Research Symposium, which takes place next week (Thursday, May 19). She is in Alejandra San Martin’s lab, studying NADPH oxidase enzymes and how they regulate cell migration.

Valdivia submitted this image of mouse embryonic fibroblasts forming focal adhesions, points of contact of the cell with the extracellular matrix. Focal adhesions allow the cells to adhere and migrate.

Explanation: Red is for paxillin, a protein concentrated in focal adhesions. Green is phalloidin, a toxin from mushrooms that binds one type of the cytoskeletal protein actin, seen here as stress fibers. Blue is DNA, showing the cells’ nuclei.

 

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Football metabolomics

Following on the recent announcement of the Atlanta Hawks training center, here’s a Nov. 2015 research paper from Emory’s sports cardiologist Jonathan Kim, published in Annals of Sports Medicine and Research.

Jonathan Kim, MD

Kim and colleagues from Emory Clinical Cardiovascular Research Institute studied blood samples from 15 freshman football players at Georgia Tech before and after their first competitive season. The researchers had the help of metabolomics expert Dean Jones. Kim has also previously studied blood pressure risk factors in college football players.

On average, football players’ resting heart rate went down significantly (72 to 61 beats per minute), but there were no significant changes in body mass index or blood pressure. The research team observed changes in players’ amino acid metabolism, which they attribute to muscle buildup.

This finding may seem obvious, but imagine what a larger, more detailed analysis could do: start to replace locker room myths and marketing aimed at bodybuilders with science. This was a small, preliminary study, and the authors note they were not able to assess diet or nutritional supplementation. Read more

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Food deserts and cardiovascular risk

Heval Mohamed Kelli, MD got some attention at the American College of Cardiology meeting over the weekend with his work on food deserts — low-income areas distant from access to healthy food.

As Medscape summarized the results: “Atlantans living in disadvantaged areas where the nearest supermarket was a mile or more away were more likely to have hypertension or hyperlipidemia, smoke, be obese, and have higher levels of systemic inflammatory markers and stiffer arteries.”

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Kelli at Clarkston Health Clinic, which Emory doctors helped establish in 2015. Clarkston is considered a “food desert”.

For more on Kelli’s journey from Syrian refugee to Clarkston, GA teenager to Emory cardiology researcher, check out this feature in Emory Magazine.

His research was conducted through the Emory Clinical Cardiovascular Research Institute, using information on 712 community participants from the META-Health study and 709 Emory/Georgia Tech employees from the Predictive Health study.

Three possibilities for further investigation:

*Income, education, race and geography are intertwined. “Whether lack of access to healthy foods, low income, or low education is driving these processes needs to be further studied,” Kelli and colleagues concluded.

*For detailed maps of food deserts, not just in Atlanta and/or determined using different criteria, the U.S. Department of Agriculture makes it possible.

*This Atlantic article makes the point that “when it comes to nutrition access, the focus should be on poverty, not grocery-store location.” You can lead people to the supermarket (or build one close to where they live), but you can’t make them eat a Mediterranean diet. Studies from Los Angeles showed that obesity increased more in some neighborhoods, even despite a ban on new fast food restaurants.

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When cardiac risk biomarkers will become really useful (and save money?)

The news is awash in studies of cholesterol-lowering statins and a much-anticipated (and expensive) class of drugs called PCSK9 inhibitors. Clinical trials show that now-generic (and cheap) statins reduce the risk of heart attack and stroke, although some patients report they can’t tolerate them. The data is still to come showing whether PCSK9 inhibitors have the same risk-lowering effect, as opposed to their effects on LDL cholesterol, which are robust.

When /if doctors have to start deciding who should take drugs that cost thousands of dollars a year and who shouldn’t, biomarkers may come in handy. How about a panel of markers like the one studied by Emory cardiologist Arshed Quyyumi, MD and colleagues?

At the recent American College of Cardiology meeting in Chicago, research fellow Salim Hayek, MD reported on a five-marker panel and how it could predict the risk of cardiovascular events (that is: death, heart attack, hospitalization for heart failure) in a group of patients who underwent cardiac catheterization at Emory hospitals.

The five biomarkers are: C-reactive protein (CRP, measures inflammation), suPAR (soluble urokinase-type plasminogen activator receptor or suPAR, predicts kidney disease), fibrin degradation products (FDP: blood coagulation), heat-shock protein-70 (HSP70, cellular stress) and troponin (hs-TnI, cardiac muscle damage). Data on three of these were published in 2013.

The Emory team keeps adding more biomarkers, and the ability of the accumulated information to add to what doctors can figure out easily — the Framingham score and its successors — becomes stronger.

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ACC 2016: Stem cell study sees improved heart failure outcomes

Patients with heart failure who received an experimental stem cell therapy experienced a reduced rate of death, hospitalization and unplanned clinic visits over the next year compared to a placebo group, according to results presented Monday at the American College of Cardiology meeting in Chicago.

The results of the ixCELL-DCM study were published online Monday by The Lancet. It was reportedly the largest cell therapy study done in patients with heart failure so far (58 treated vs 51 placebo).

Emory University School of Medicine investigators led by Arshed Quyyumi, MD, and their patients participated in the study, and Emory was one of the largest enrolling sites. Lead authors were Timothy Henry, MD of Cedars-Sinai Heart Institute in Los Angeles and Amit Patel, MD of the University of Utah.

“For the first time, a clinical trial has shown that administration of a cellular therapeutic results in an improvement in cardiac outcomes based on a prespecified analysis,” an editorial accompanying the paper in The Lancet says.

This study, which was sponsored by Vericel Corporation, was phase II, meaning that a larger phase III study will be needed before FDA approval. Read more

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ACC 2016: Elevated troponin linked to mental stress ischemia

Some people with heart disease experience a restriction of blood flow to the heart in response to psychological stress. Usually silent (not painful), the temporary restriction in blood flow, called ischemia, is an indicator of greater mortality risk.

Cardiologists at Emory University School of Medicine have discovered that people in this group tend to have higher levels of troponin — a protein whose increased presence in the blood that is a sign of recent damage or stress to the heart muscle– all the time, independently of whether they are experiencing stress or chest pain at that moment.

The results were presented Sunday by cardiology research fellow Muhammad Hammadah, MD at the American College of Cardiology meeting in Chicago, as part of the Young Investigator Awards competition. Hammadah works with Arshed Quyyumi, MD, and Viola Vaccarino, MD, PhD, and colleagues at the Emory Clinical Cardiovascular Research Institute.

“Elevated troponin levels in patients with coronary artery disease may be a sign that they are experiencing repeated ischemic events in everyday life, with either psychological or physical triggers,” Hammadah says.

Doctors test for troponin in the blood to tell whether someone has recently had a heart attack. But the levels seen in this study were lower than those used to diagnose a heart attack: less than a standard cutoff of 26 picograms per milliliter, in a range that only a high-sensitivity test for troponin could detect.

In a separate study, Emory investigators have shown that elevated troponin levels (especially: more than 10 pg/mL)  predict mortality risk over the next few years in patients undergoing cardiac catheterization, even in those without apparent coronary artery disease.

There is already a lot of information available for doctors about the significance of elevated troponin. It has even been detected at elevated levels after strenuous exercise in healthy individuals. One recent study suggested that low levels of troponin could be used to rule out heart attack for patients in the emergency department.

More information about the mental stress ischemia study: Read more

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Rare inherited musculoskeletal disorder illustrates broader themes

More than fifteen years ago, Emory geneticist William Wilcox was a visiting professor in Montevideo, Uruguay. There he worked with local doctors, led by Roberto Quadrelli, to study a family whose male members appeared to have an X-linked inherited disorder involving heart disease and musculoskeletal deformities.

In March 2016, Wilcox and his colleagues reported in Circulation: Cardiovascular Genetics that they had identified the genetic mutation responsible for the disorder, called “Uruguay syndrome.” His former postdoc Yuan Xue, now a lab director at Fulgent Diagnostics and a course instructor in Emory’s genetics counseling program, was the lead author.

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William Wilcox, MD, PhD

“It took many years and advances in technology to move the molecular definition from localization on the X chromosome to a specific mutation,” Wilcox says.

Still, with current DNA sequencing technology, this kind of investigation and genetic discovery takes place all the time. Why focus on this particular paper or family?

*This gene is a big tent — Mutations in FHL1, the gene that is mutated in the Uruguayan family, are responsible for several types of inherited muscle disorders, which differ depending on the precise mutation. In 2013, an international workshop summarized current knowledge on this family of diseases.

Some forms of FHL1 mutation are more severe, such as reducing body myopathy, which can have early childhood onset leading to respiratory failure. Other forms are less severe. While some men in the Uruguayan family died early from heart disease, the man who Wilcox helped treat is now teaching high school and his hypertrophic cardiomyopathy is stable on a beta blocker.

“Studying a sample of his muscle proved that we had the right gene and some of what the mutation does,” Wilcox says.

*Studying rare mutations can lead to blockbuster drugs – The discovery of potent yet expensive cholesterol-lowering PCSK9 inhibitors, which grew out of the study of familial hypercholesterolemia, is a prominent example.

FHL1 regulates muscle growth by interacting with several other proteins. Probing its function may yield insights with implications for the treatment of muscular dystrophies and possibly for athletes. As NPR’s Jon Hamilton explains, the development of myostatin inhibitors, intended to help people with muscle-wasting diseases, has led to concern about them becoming the next generation of performance-enhancing drugs. Read more

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