Circadian rhythms go both ways: in and from retina

Removal of Bmal1 accelerates the deterioration of vision that comes with Read more

Genomics plus human intelligence

The power of gene sequencing to solve puzzles when combined with human Read more

'Master key' microRNA has links to both ASD and schizophrenia

Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few "master keys," risk genes that sit at the center of a network of genes important for brain function. Researchers at Emory and the Chinese Academy of Sciences have created mice partially lacking one of those master keys, called MIR-137, and have used them to identify an angle on potential treatments for ASD. The results were published this Read more

Cancer

Nox-ious link to cancer Warburg effect

At Emory, Kathy Griendling’s group is well known for studying NADPH oxidases (also known as Nox), enzymes which generate reactive oxygen species. In 2009, they published a paper on a regulator of Nox enzymes called Poldip2. Griendling’s former postdoc, now assistant professor, Alejandra San Martin has taken up Poldip2.

Griendling first came to Nox enzymes from a cardiology/vascular biology perspective, but they have links to cancer. Nox enzymes are multifarious and it appears that Poldip2 is too. As its full name suggests, Poldip2 (polymerase delta interacting protein 2) was first identified as interacting with DNA replication enzymes.  Poldip2 also appears in mitochondria, indirectly regulating the process of lipoylation — attachment of a fatty acid to proteins anchoring them in membranes. That’s where a recent PNAS paper from San Martin, Griendling and colleagues comes in. It identifies Poldip2 as playing a role in hypoxia and cancer cell metabolic adaptation.

Part of the PNAS paper focuses on Poldip2 in triple-negative breast cancer, more difficult to treat. In TNBC cells, Poldip2’s absence appears to be part of the warped cancer cell metabolism known as the Warburg effect. Lab Land has explored the Warburg effect with Winship’s Jing Chen.

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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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Life-saving predictions from the ICU

It’s similar to the “precogs” who predict crime in the movie Minority Report, but for sepsis, the deadly response to infection. That’s how Tim Buchman, director of the Emory Critical Care Center, described an emerging effort to detect and ward off sepsis in ICU patients hours before it starts to make their vital signs go haywire.

As landmark clinical studies have documented, every hour of delay in giving someone with sepsis antibiotics increases their risk of mortality. So detecting sepsis as early as possible could save lives. Many hospitals have developed “sniffer” systems that monitor patients for sepsis risk. See our 2016 feature in Emory Medicine for more details.

What Shamim Nemati and his colleagues, including bioinformatics chair Gari Clifford, have been exploring is more sophisticated. A vastly simplified way to summarize it is: if someone has a disorderly heart rate and blood pressure, those changes can be an early indicator of sepsis.* It requires continuous monitoring – not just once an hour. But in the ICU, this can be done. The algorithm uses 65 indicators, such as respiration, temperature, and oxygen levels — not only heart rate and blood pressure. See below.

Example patient graph. Green = SOFA score. Purple = Artificial Intelligence Sepsis Expert (AISE) score. Red = official definition of sepsis. Blue = antibiotics. Black + red = cultures.    Around 4 pm on December 20, roughly 8 hr prior to any change in the SOFA score, the AISE score starts to increase. The top contributing factors were slight changes in heart rate, respiration, and temperature, given that the patient had surgery in the past 12hr with a contaminated wound and was on a mechanical ventilator. Close to midnight on December 21, other factors show abnormal changes. Five hours later, the patient met the Sepsis-3 definition of sepsis.

As recently published in the journal Critical Care Medicine, Nemati’s algorithm can predict sepsis onset – with some false alarms – 4, 8 even 12 hours ahead of time. No predictor is going to be perfect, Nemati says. The paper lays out specificity, sensitivity and accuracy under various timelines. They get to an AUROC (area under receiving operating characteristic) performance of 0.83 to 0.85, which this explainer web site rates as good (B), and is better than any other previous sepsis predictor. Read more

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Before the cardiologist goes nuclear w/ stress #AHA17

Exercise stress testing to diagnose heart disease has a long history. This year, cardiologists can celebrate the 50-year anniversary of a study connecting abnormal stress test results and obstructive coronary artery disease (CAD).

The basic stress test procedure can involve walking on a tilting treadmill as the heart is monitored via electrocardiogram. A variant called the nuclear stress test involves introducing a radioactive tracer into the body to visualize alterations in blood flow within the heart.

Some stress tests are considered inappropriate, leading to additional medical costs. Arshed Quyyumi and colleagues from Emory Clinical Cardiovascular Research Institute presented research on Sunday at the American Heart Association Scientific Sessions meeting on the use of a blood test along with an exercise stress test. First author Bryan Kindya is a 2017-18 internal medicine resident.

The blood test detects troponin, a sign of recent damage to the cardiac muscle. Very high levels indicate that someone is having a heart attack. As testing for troponin has become more sensitive in recent years, the implications of lower but still detectable troponin levels need to be backed up by follow-up outcomes. That’s what the Emory data can provide.

Quyyumi’s team found that more than 25 percent of CAD patients will have troponin levels below a certain cut-off (2.45 picograms per milliliter), predicting that they have a low risk of having heart problems during a stress test or adverse events (hospitalization/heart attack/death) over the next three years.

The researchers conclude that measuring troponin in CAD patients before embarking on stress testing “may provide major cost-savings.” Disclosure: the research was done in cooperation with Abbott Labs, the maker of the high-sensitivity troponin test.

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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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How race + TBI experience affect views of informed consent

The upcoming HBO movie of The Immortal Life of Henrietta Lacks reminds us that biomedical research has a complex legacy, when it comes to informed consent and people of color.

A paper from Emory investigators, published in AJOB Empirical Bioethicstouches on related current issues. The paper examines how race and close experience with traumatic brain injury affect study participants’ views of informed consent in clinical research.

This emerged from a study of community consultation for EFIC (exception from informed consent), in connection with a nationwide clinical trial of progesterone for traumatic brain injury (TBI). EFIC describes clinical research performed when the normal process of obtaining patients’ informed consent is not possible, because of emergency conditions such as seizures or TBI. Before such studies can be undertaken, the FDA calls for protective procedures and community consultation.

In this case, researchers surveyed 2612 people at 12 sites involved in the TBI study. The survey asked about attitudes toward the EFIC aspects of the study and also asked if they had personal experience with traumatic brain injury – either themselves or someone close to them. How that personal connection affected their responses was influenced by race.

Key paragraph from discussion:

Among white participants, increased levels of acceptance of EFIC were found among those with any connections to TBI. On the other hand, among participants identifying as black or other nonwhite races, there was decreased acceptance of EFIC enrollment among TBI patients and no increase in acceptance among those with a family member/loved one with TBI. The fact that black and white participants with no personal TBI experience or with a more distant connection to TBI had similar acceptance rates suggests that baseline acceptance of EFIC among these two groups is fairly similar and that the experience with the condition itself plays a role in driving the observed differences…

Read more

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To explain cancer biology, use metaphors

Using metaphors to explain biomedical concepts is our bread and butter. That’s why we were tickled to see a recent paper from Winship Cancer Institute bioethicist Rebecca Pentz and colleagues, titled:

Using Metaphors to Explain Molecular Testing to Cancer Patients

Pentz’s team systematically evaluated something that science writers and journalists try to do all the time (and not always well). And they did so with actual conversations between doctors and patients at Winship. The first author of the paper, published in The Oncologist, was medical student Ana Pinheiro.

The researchers studied 66 conversations with nine oncologists. In 25 of those conversations, patients reported that they were able to hear a metaphor. Here’s one example:

“We try to figure out what food makes this kind of cancer grow. For this cancer, the food was estrogen and progesterone. So we’re going to focus on blocking the hormones, because that way we starve the cancer of its food.”

The paper lists all 17 (bus driver, boss, switch, battery, circuit, broken light switch, gas pedal, key turning off an engine, key opening a lock, food for growth, satellite and antenna, interstate, alternate circuit, traffic jam, blueprint, room names, Florida citrus) and how they were used to explain eight cancer-related molecular testing terms.

When patients were asked about the helpfulness of a metaphor that was used, 85 percent of the time they demonstrated understanding and said it was helpful. So let the metaphors fly!

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