The journey of a marathon sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to follow. What they found could provide benefits for patients with the genetic disease myotonic dystrophy (DM) and possibly the sleep disorder idiopathic hypersomnia (IH).

The classic symptom for DM is: someone has trouble releasing their grip on a doorknob. However, the disease does not only affect the muscles. Clinicians have recognized for years that DM can result in disabling daytime sleepiness and sometimes cognitive impairments. At the Myotonic Dystrophy Foundation meeting in September, a session was held gathering patient input on central nervous system (CNS) symptoms, so that future clinical trials could track those symptoms more rigorously.

Emory scientists are investigating this aspect of DM. Cell biology chair Gary Bassell was interested in the disease, because it’s a triplet repeat disorder, similar to fragile X syndrome, yet the CNS mechanisms and symptoms are very different. In DM, an expanded triplet or quadruplet repeat produces toxic RNA, which disrupts the process of RNA splicing, affecting multiple cell types and tissues.

Rye at San Francisco myotonic dystrophy meeting. Photo courtesy of Hypersomnia Foundation.

Neurologist and sleep specialist David Rye also has become involved. Recall Rye’s 2012 paper in Science Translational Medicine, which described a still-mysterious GABA-enhancing substance present in the spinal fluid of some super-sleepy patients. (GABA is a neurotransmitter important for regulating sleep.)

In seven of those patients, his team tested the “wake up” effects of flumazenil, conventionally used as an antidote to benzodiazepines. One of those patients was an Atlanta lawyer, whose recovery was later featured in the Wall Street Journal and on the Today Show. It turns out that another one of the seven, whose alertness increased in response to flumazenil, has DM.

In an overnight sleep exam, this man slept for 12 hours straight – the longest of the seven. But an IH diagnosis didn’t fit, because in the standard “take a nap five times” test, he didn’t doze off very quickly. He became frustrated with the stimulants he was given and sought treatment elsewhere, Rye says. Lab Land doesn’t have all the details of this patient’s history, but eventually he was diagnosed with DM, which clarified his situation. Read more

Posted on December 1, 2017 by Quinn Eastman in Neuro Leave a comment

A push for reproducibility in biomedical research

Editor’s note: guest post from Neuroscience graduate student Erica Landis.

Neuroscience graduate student Erica Landis

Evidence is increasing that lack of reproducibility, whatever the cause, is a systemic problem in biomedical science. While institutions like the NIH and concerned journal editors are making efforts to implement more stringent requirements for rigorous and reproducible research, scientists themselves must make conscious efforts to avoid common pitfalls of scientific research. Here at Emory, several scientists are making greater efforts to push forward to improve scientific research and combat what is being called “the reproducibility crisis.”

In 2012, C. Glenn Begley, then a scientist with the pharmaceutical company Amgen, published a commentary in Nature on his growing concern for the reproducibility of preclinical research. Begley and his colleagues had attempted to replicate 53 published studies they identified as relevant to their own research into potential pharmaceuticals. They found that only 6 of the 53 publications could be replicated; even with help from the original authors. Similar studies have consistently found that greater than 50 percent of published studies could not be replicated. This sparked a period of great concern and questioning for scientists. It seemed to Begley and others that experimenter bias, carelessness, poor understanding of statistics, and the career-dependent scramble to publish contributes to a misuse of the scientific method. These factors contribute to what is now called the reproducibility crisis. In April 2017, Richard Harris published Rigor Mortis, a survey of the problem in preclinical research, which has kept the conversation going and left many wondering what the best solution to these issues could be. To combat the reproducibility crisis, Harris argues that funding agencies, journal editors and reviewers, research institutions, and scientists themselves all have a role to play.

Posted on November 27, 2017 by Quinn Eastman in Uncategorized Leave a comment

Exosomes as potential biomarkers of radiation exposure

Kishore Kumar Jella, PhD

Winship Cancer Institute postdoc Kishore Kumar Jella has been invited to speak at the NATO advanced research workshop “BRITE (Biomarkers of Radiation In the Environment): Robust tools for Risk Assessment” in Yerevan, Armenia, on 28-30 November, 2017. The workshop brings together leading international experts to evaluate currently and developing radiation biomarkers for environmental applications.

Jella works in the Departments of Biochemistry and Radiation Oncology under the direction of Professors William S. Dynan and Mohammad K. Khan. He will speak on “Exosomes as Radiation Biomarkers”. He will describe how radiation influences exosome production and how these exosomes influence the immune system. The work has applications both to radiation carcinogenesis and combination radio-immunotherapy.

Jella is supported in part by a grant from the National Aeronautics and Space Administration to Dynan.

Exosomes are nano-sized membrane-clothed capsules containing proteins and RNA that are thought to facilitate cell-cell communcation. They were previously implicated in the ability of cancer cells to influence healthy neighbor cells, and have also been proposed as anti-cancer therapeutic vehicles. Jella’s previous research on exosomes and radiation-induced bystander signaling was published in Radiation Research in 2014.

Posted on November 21, 2017 by Quinn Eastman in Cancer Leave a comment

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.

Posted on November 15, 2017 by Quinn Eastman in Heart Leave a comment

Virus hunting season open

New viruses have been popping up in industrial water-cooling towers, in Antarctica and salty deserts. Erwin van Meir, from Winship Cancer Institute of Emory University, and his collaborators managed to find two inside someone’s metastatic tumor.

Working with Terry Fei Fan Ng and Eric Delwart from UCSF, Van Meir identified two new species of anellovirus, a family of viruses first discovered in the 1990s. The new viruses come from a patient with a melanoma that had metastasized to the brain and was operated on at Emory University Hospital.

The results were recently published in Oncotarget.

“We have no evidence that these two viruses were involved in the tumor’s formation, but the data are proof of principle that the metagenomics method used can discover more unknown viruses in human brain tumors,” Van Meir says.

Erwin Van Meir, PhD

Metagenomics is the study of genetic material obtained directly from the environment. The approach is often used to study bacteria, but it is equally valid for viruses. In this paper, investigators used enzymes to chew up human and bacterial DNA, enriching for viral DNA protected by the viral capsid.

Estimates from the USAID’s PREDICT program point to thousands or even millions of viruses, present in mammals and birds, which remain unknown to humans. According to Annual Review of Virology from this summer, Viruses with Circular Single-Stranded DNA Genomes are Everywhere! – and that includes Anelloviridae, for which there is “still no convincing direct causal relation to any specific disease.”

Anelloviruses are relatively primitive in that they do not encode a viral polymerase (the enzyme that copies DNA) and thus need to rely upon the host cell and replicate inside the nucleus. The new ones were named Torque teno mini virus Emory1 (TTMV Emory1) and Torque teno mini virus Emory2 (TTMV Emory2). The research team gave a nod to Emory by using its colors in the virus genome cartoons accompanying the publication. Read more

Posted on November 14, 2017 by Quinn Eastman in Cancer Leave a comment

#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

Posted on November 14, 2017 by Quinn Eastman in Heart Leave a comment

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

Posted on October 23, 2017 by Quinn Eastman in Heart Leave a comment

Skin disease studies go deep: depression/inflammation insight

The placebo effect plays a big role in clinical trials for mood disorders such as depression. Emory psychiatrist Andy Miller hit upon something several years ago that could clear a path around the placebo effect.

Miller and his colleagues have been looking at the connection between inflammation and depression, whose evolutionary dimensions we have previously explored. They’ve examined the ability of inflammation-inducing treatments for hepatitis C and cancer to trigger symptoms of depression, and have shown that the anti-inflammatory drug infliximab (mainly used for rheumatoid arthritis) can resolve some cases of treatment-resistant depression. [Lots of praise for Miller in this September 2017 Nature Medicine feature.]

A recent paper in Psychotherapy and Psychosomatics from Miller and psychiatry chair Mark Rapaport looks at clinical trials testing an anti-inflammatory drug against psoriasis, to see whether participants’ depressive symptoms improved. This sidesteps a situation where doctors’ main targets are the patients’ moods.

When it comes to approving new antidepressants, the FDA is still probably going to want a frontal assault on depression, despite provisions in the 21^st Century Cures Act to broaden the types of admissible evidence.

“These studies emphasize how difficult it is to interpret findings when these drugs are treating more than one problem,” Miller says. “Better to have a simpler study with just depression.”

Still, this line of research could clarify who could benefit from anti-inflammatory treatments and illuminate viable biomarkers and pathways. Two studies now underway at Emory specifically recruit patients with high levels of the inflammatory marker CRP, which Miller’s previous study showed was helpful in predicting response to infliximab.

The new paper results from a collaboration with Eli Lilly. Lilly’s ixekizumab (commercial name: Taltz) is an antibody against the cytokine IL-17A, used to treat moderate to severe psoriasis. Taltz was approved by the FDA in 2016, after clinical trials published in the New England Journal of Medicine. Read more

Posted on October 20, 2017 by Quinn Eastman in Immunology, Neuro Leave a comment

New insight into how brain cells die in Alzheimer’s and FTD

Removal of a regulatory gene called LSD1 in adult mice induces changes in gene activity that look unexpectedly like Alzheimer’s disease, scientists have discovered.

Researchers also discovered that LSD1 protein is perturbed in brain samples from humans with Alzheimer’s disease and frontotemporal dementia (FTD). Based on their findings in human patients and mice, the research team is proposing LSD1 as a central player in these neurodegenerative diseases and a drug target.

David Katz, PhD

The results were published Oct. 9 in Nature Communications.

In the brain, LSD1 (lysine specific histone demethylase 1) maintains silence among genes that are supposed to be turned off. When the researchers engineered mice that have the LSD1 gene snipped out in adulthood, the mice became cognitively impaired and paralyzed. Plenty of neurons were dying in the brains of LSD1-deleted mice, although other organs seemed fine. However, they lacked aggregated proteins in their brains, like those thought to drive Alzheimer’s disease and FTD.

“In these mice, we are skipping the aggregated proteins, which are usually thought of as the triggers of dementia, and going straight to the downstream effects,” says David Katz, PhD, assistant professor of cell biology at Emory University School of Medicine. Read more

Posted on October 18, 2017 by Quinn Eastman in Neuro Leave a comment

2B4: potential immune target for sepsis survival

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to infection.

2B4 is an inhibitory molecule found on immune cells. You may have heard of PD1, which cancer immunotherapy drugs block in order to re-energize the immune system. 2B4 appears to be similar; it appears on exhausted T cells after chronic viral infection, and its absence can contribute to autoimmunity.

In their new paper in Journal of Immunology, Mandy Ford, Craig Coopersmith and colleagues show that 2B4 levels are increased on certain types of T cells (CD4+ memory cells) in human sepsis patients and in a mouse model of sepsis called CLP (cecal ligation + puncture). Genetically knocking out 2B4 or blocking it with an antibody both reduce mortality in the CLP model. The effect of the knockout is striking: 82 percent survival vs 13 percent for controls.

How does it work? When fighting sepsis, 2B4 knockout animals don’t have reduced bacterial levels, but they do seem to have CD4+ T cels that survive better. CD4+ T cells, especially memory cells, get killed in large numbers during sepsis, and this is thought to contribute to mortality. Read more

Posted on September 26, 2017 by Quinn Eastman in Immunology Leave a comment

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