Mysterious DNA modification important in fly brain

Drosophila, despite being a useful genetic model of development, have very little DNA methylation on C. What they do have is methylation on A (technically, N6-methyladenine), although little was known about what this modification did for Read more

Where it hurts matters in the gut

What part of the intestine is problematic matters more than inflammatory bowel disease subtype (Crohn’s vs ulcerative colitis), when it comes to genetic activity signatures in pediatric Read more

Overcoming cisplatin resistance

Cisplatin was known to damage DNA and to unleash reactive oxygen species, but the interaction between cisplatin and Mek1/cRaf had not been observed Read more

cardiology

Stem cells driven into selective suicide

The term “stem cell” is increasingly stretchy. Orthopedic specialists have been using it when referring to bone marrow concentrate or platelet rich plasma, which are marketed as treatments for joint pain. At Lab Land, we have an interest in pluripotent stem cells, which can differentiate into many types of tissues.

For many applications, the stem cells are actually impurities that need to be removed, because pluripotent stem cells are capable of becoming teratomas, a type of tumor. 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.

Cardiologist and stem cell expert Chunhui Xu has been continuing a line of investigation on this topic. In a recent paper in ACS Chemical Biology, her team showed that “suicide-inducing molecules” can eliminate undifferentiated stem cells from a mixture of cells. This stem-cell-derived mixture was mostly cardiac muscle cells or their progenitors, which Xu’s team wants to use for therapeutic purposes.

Other labs have used metabolic selection – depriving cells of glucose and giving them only lactate –as a selective method for eliminating stem cells from cardiac muscle cultures. This paper shows that the “selective suicide” method works for early-stage differentiation cultures, containing cardiac progenitors, while the metabolic method works only for late-stage cultures contains beating cardiomyocytes.

Read more

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Blue plate special: express delivery to the heart

The anti-arrhythmia drug amiodarone is often prescribed for control of atrial fibrillation, but can have toxic effects upon the lungs, eyes, thyroid and liver. Emory and Georgia Tech scientists have developed a method for delivering amiodarone directly to the heart in an extended release gel to reduce off-target effects.

The results were published in Circulation: Arrhythmia and Electrophysiology.

The senior author is Rebecca Levit, MD, assistant professor of medicine (cardiology) at Emory University School of Medicine and adjunct in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Graduate student Jose Garcia – part of co-author Andres Garcia’s lab at Georgia Tech — and Peter Campbell, MD are the first authors.

An amiodarone-containing gel was applied to the outside of the heart by a minimally invasive procedure. After a one-time delivery, the gel could reduce the duration of atrial fibrillation and the likelihood of its development for a month in a pig model. The researchers were also able to show that amiodarone did not have toxic effects on the pigs’ lungs.

As noted in the book Off-label prescribing – Justifying unapproved medicine, amiodarone is “one of the very few drugs approved by the FDA in modern times without rigorous randomized clinical trials.” Read more

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For nanomedicine, cell sex matters

The biological differences between male and female cells may influence their uptake of nanoparticles, which have been much discussed as specific delivery vehicles for medicines.

Vahid Serpooshan, PhD

New Emory/Georgia Tech BME faculty member Vahid Serpooshan has a recent paper published in ACS Nano making this point. He and his colleagues from Brigham and Women’s Hospital and Stanford/McGill/UC Berkeley tested amniotic stem cells, derived from placental tissue. They found that female amniotic cells had significantly higher uptake of nanoparticles (quantum dots) than male cells. The effect of cell sex on nanoparticle uptake was reversed in fibroblasts. The researchers also found out that female versus male amniotic stem cells exhibited different responses to reprogramming into induced pluripotent stem cells (iPSCs).

Female human amniotic stem cells with nanoparticles .Green: quantum dots/ nanoparticles; red: cell staining; blue: nuclei.

“We believe this is a substantial discovery and a game changer in the field of nanomedicine, in taking safer and more effective and accurate steps towards successful clinical applications,” says Serpooshan, who is part of the Department of Pediatrics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

Serpooshan’s interests lie in the realm of pediatric cardiology. His K99 grant indicates that he is planning to develop techniques for recruiting and activating cardiomyoblasts, via “a bioengineered cardiac patch delivery of small molecules.” Here at Emory, he joins labs with overlapping interests such as those of Mike Davis, Hee Cheol Cho and Nawazish Naqvi. Welcome!

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Elevated (but still low) troponin as a long term cardio biomarker

This weekend (March 10) at the American College of Cardiology meeting, data will emerge on whether expensive and much-discussed PCSK9 inhibitors can lower the risk of heart disease as much as they reduce LDL cholesterol.

To help doctors decide who should take cholesterol-lowering drugs that cost thousands of dollars a year, the focus of discussion could fall on risk models, such as the Framingham score and its successors, or other biomarkers besides various forms of cholesterol. What a coincidence! We have experts on those topics at Emory Clinical Cardiovascular Research Institute: ECCRI co-director Arshed Quyyumi, MD and Laurence Sperling, MD, Director of Preventive Cardiology at the Emory Clinic.

Cardiologists led by Quyyumi have a recent paper in Journal of the American Heart Association looking at troponin as a long-term cardiovascular disease biomarker. Troponin is familiar to cardiologists because it is a sign of acute damage to the heart muscle. If someone with chest pain goes to the emergency department of a hospital, a test for troponin in the blood can say whether a heart attack occurred.

However, as clinical tests for troponin have become more sensitive in the last decade, interpretation has moved past just a “yes/no” question. The levels of troponin now detectable are much smaller than those used to confirm a heart attack. Elevated troponin can be detected in all sorts of situations where the heart is under stress, including after strenuous exercise in healthy individuals. The “optimal cutoff” the Emory authors use in some of their statistical analyses is 5.2 picograms per milliliter. This graph, derived from a 2011 Circulation paper, illustrates just how low that is. Read more

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When circulating ambulances disappear

Someone driving around a city on a regular basis will see ambulances. At times they’re going somewhere fast; sometimes they’re just driving. What if, on a given day, fewer ambulances are visible?

One possible conclusion might be: the ambulances are away responding to a group of people who need help. This effect resembles what Arshed Quyyumi and colleagues from Emory Clinical Cardiovascular Research Institute observed in a recent paper, published in the Journal of the American Heart Association.

Arshed Quyyumi, MD

Quyyumi’s team looked at progenitor cells, which circulate in the blood and are attracted to sites of injury.  In a group of 356 patients with stable coronary artery disease, the researchers saw that some (31 percent) had “ExMI” – exercise-mediated myocardial ischemia. That means impairments in blood flow were visible via cardiac imaging under the stress of exercise. This is a relatively mild impairment; participants did not report chest pain. This paper emerges from the MIPS (Mental Stress Ischemia Prognosis) study, 2011-2014.

The ambulance-progenitor cell analogy isn’t perfect; exercise, generally a good thing, increases progenitor cell levels in the blood, says co-first author and cardiology fellow Muhammad Hammadah. The study supports the idea that patients with coronary artery disease may benefit from cardiac rehab programs, which drive the progenitor cells into the ischemic tissue, so they can contribute into vascular repair and regeneration. Read more

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Calming an electrical storm in the heart

AT = anterior tubercle of C6, C = carotid artery, LC = longus colli muscle, T = thyroid gland, IJ = internal jugular vein, compressed

The most recent issue of Emory Medicine features a story that first came to Lab Land’s attention when it was presented as an abstract at the 2017 American College of Cardiology Scientific Sessions meeting.

Emory doctors were challenged by a patient who repeatedly developed cardiac arrhythmias, called “refractory electrical storm.” They used a local anesthesia procedure called stellate ganglion block — normally used for complex pain — to calm the storm. Cardiac electrophysiologist Michael Lloyd, who likes solving puzzles, was the one who decided to try it.

Emory anesthesiologist Boris Spektor provided this ultrasound picture of the procedure. Stellate ganglion block is also being tested for conditions such as PTSD. Please read the whole story!

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#AHA17 highlight: cardiac pacemaker cells

At the American Heart Association Scientific Sessions meeting this week, Hee Cheol Cho’s lab is presenting three abstracts on pacemaker cells. These cells make up the sinoatrial node, which generates electrical impulses driving our heart beats. Knowing how to engineer them could enhance cardiologists’ ability to treat arrhythmias, especially in pediatric patients, but that goal is still some distance away.

Just a glimpse of the challenge comes from graduate student Sandra Grijalva’s late breaking oral abstract describing “Induced Pacemaker Spheroids as a Model to Reverse-Engineer the Native Sinoatrial Node”, which was presented yesterday.

Cho has previously published how induced pacemaker cells can be created by introducing the TBX18 gene into rat cardiac muscle cells. In the new research, when a spheroid of induced pacemaker cells was surrounded by a layer of cardiac muscle cells, the IPM cells were able to drive the previously quiescent nearby cells at around 145 beats per minute. [For reference, rats’ hearts beat in living animals at around 300 beats per minute.] Read more

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Long-lasting blood vessel repair in animals via stem cells

Stem cell researchers at Emory University School of Medicine have made an advance toward having a long-lasting “repair caulk” for blood vessels. The research could form the basis of a treatment for peripheral artery disease, derived from a patient’s own cells. Their results were recently published in the journal Circulation.

A team led by Young-sup Yoon, MD, PhD developed a new method for generating endothelial cells, which make up the lining of blood vessels, from human induced pluripotent stem cells.. When endothelial cells are surrounded by a supportive gel and implanted into mice with damaged blood vessels, they become part of the animals’ blood vessels, surviving for more than 10 months.

“We tried several different gels before finding the best one,” Yoon says. “This is the part that is my dream come true: the endothelial cells are really contributing to endogenous vessels. When I’ve shown these results to people in the field, they say ‘Wow.'”

Previous attempts to achieve the same effect elsewhere had implanted cells lasting only a few days to weeks, although those studies mostly used adult stem cells, such as mesenchymal stem cells or endothelial progenitor cells, he says.

“When cells are implanted on their own, many of them die quickly, and the main therapeutic benefits are from growth factors they secrete,” he adds. “When these endothelial cells are delivered in a gel, they are protected. It takes several weeks for most of them to migrate to vessels and incorporate into them.” Read more

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Blood vessels and cardiac muscle cells off the shelf

Tube-forming ability of purified CD31+ endothelial cells derived from induced pluripotent stem cells after VEGF treatment.

Chunhui Xu’s lab in the Department of Pediatrics recently published a paper in Stem Cell Reports on the differentiation of endothelial cells, which line and maintain blood vessels. Her lab is part of the Emory-Children’s-Georgia Tech Pediatric Research Alliance. The first author was postdoc Rajneesh Jha.

This line of investigation could eventually lead to artificial blood vessels, grown with patients’ own cells or “off the shelf,” or biological/pharmaceutical treatments that promote the regeneration of damaged blood vessels. These treatments could be applied to peripheral artery disease and/or coronary artery disease.

Xu’s paper concerns the protein LGR5, part of the Wnt signaling pathway. The authors report that inhibiting LGR5 steers differentiating pluripotent stem cells toward endothelial cells and away from cardiac muscle cells. The source iPSCs were a widely used IMR90 line.

Young-sup Yoon’s lab at Emory has also been developing methods for the generation of endothelial cells via “direct reprogramming.”

Read more

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Big data with heart, for psychiatric disorders

Imagine someone undergoing treatment by a psychiatrist. How do we know the treatment is really working or should be modified?

To assess whether the patient’s condition is objectively improving, the doctor could ask him or her to take home a heart rate monitor and wear it continuously for 24 hours. An app connected to the monitor could then track how much the patient’s heart rate varies over time and how much the patient moves.

Heart rate variability can be used to monitor psychiatric disorders

MD/PhD student Erik Reinertsen is the first author on two papers in Physiological Measurement advancing this approach, working under the supervision of Gari Clifford, interim chair of Emory’s Department of Biomedical Informatics.

Clifford’s team has been evaluating heart rate variability and activity as a tool for monitoring both PTSD (post-traumatic stress disorder) and schizophrenia. Clifford says his team’s research is expanding to look at treatment-resistant depression and other mental health issues.

For clinical applications, Clifford emphasizes that his plans focus on tracking disease severity for patients who are already diagnosed, rather than screening for new diagnoses. His team is involved in much larger studies in which heart rate data is being combined with physical activity data from smart watches, body patches, and clinical questionnaires, as well as other behavioral and exposure data collected through smartphone usage patterns.

Intuitively, heart rate variability makes sense for monitoring PTSD, because one of the core symptoms is hyperarousal, along with flashbacks and avoidance or numbness. However, it turns out that the time that provides the most information is when heart rate is lowest and study participants are most likely asleep, or at their lowest ebb during the night.

Home sleep tests generate a ton of information, which can be mined. This approach also fits into a trend for wearable medical technology, recently highlighted in STAT by Max Blau (subscription needed).

The research on PTSD monitoring grows out of work by cardiologists Amit Shah and Viola Vaccarino on heart rate variability in PTSD-discordant twin veterans (2013 Biological Psychiatry paper). Shah and Vaccarino had found that low frequency heart rate variability is much less (49 percent less) in the twin with PTSD. Genetics influences heart rate variability quite a bit, so studying twins allows those factors to be accounted for. Read more

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