What does it take to be a leader – of cancer cells?
Adam Marcus and colleagues at Winship Cancer Institute are back, with an analysis of mutations that drive metastatic behavior among groups of lung cancer cells. The findings were published this week on the cover of Journal of Cell Science, and suggest pharmacological strategies to intervene against or prevent metastasis.
Marcus and former graduate student Jessica Konen previously developed a technique for selectively labeling “leader” Read more
Researchers have identified compounds that potently activate LRH-1, which regulates the metabolism of fat and sugar. These compounds have potential for treating diabetes, fatty liver disease and inflammatory bowel Read more
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
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.
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.
â€œElevated 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,â€ 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)Â predict mortality risk over the next few years in patients undergoing cardiac catheterization, even in those without apparent coronary artery disease.
This recent paper in Circulation, from Arshed Quyyumi and colleagues at the Emory Clinical Cardiovascular Research Institute, can be seen as a culmination of, even vindication for, Â Dean Jones’ ideasÂ about redox biology.
We now know that free radicals, in the form of reactive oxygen species, can sometimes be good, even essential for life. So antioxidants that soak up free radicals to relieve you of oxidative stress: that doesn’t seem to work.
Dean Jones, who is director of Emory’s Clinical Biomarkers laboratory,Â has been an advocate for a different way of looking at oxidative stress. That is, instead of seeing cells asÂ big bags of redox-sensitive chemicals, look at cellular compartments. Look at particular antioxidant proteins and sulfur-containing antioxidant molecules such asÂ glutathione and cysteine.
That’s what theÂ Circulation paper does. Mining the Emory Cardiovascular Biobank, Quyyumi’s team shows that patients with coronary artery disease have a risk of mortality that is connected to the ratio of glutathione to cystine (the oxidized form of the amino acid cysteine).
â€œSepsis is largely a face without a name in the EMS setting, â€œ Polito says. â€œThe goal of our study was to create a tool to assist EMS providers in naming this deadly condition at the point of first medical contact. Similar to other life-threatening, time-sensitive conditions like stroke and heart attack, naming sepsis is the first step in developing coordinated care pathways that focus on delivering rapid, life-saving treatment once the patient arrives at the hospital.â€
Quick, what biomarker whose nameÂ starts with â€œcho-” is connected with cardiovascular disease? Very understandable if your first thought is â€œcholesterol.â€ Today Iâ€™d like to shift focus to a molecule with a similar name, but a very different structure: choline.
Choline, a common dietary lipid component and an essential nutrient, came to prominence in cardiology research in 2011 when researchers at the Cleveland Clinic found that choline and its relatives can contribute to cardiovascular disease in a way that depends upon intestinal bacteria. In the body, choline is part of two phospholipids that areÂ abundant in cell membranes, and is also a precursor for the neurotransmitter acetylcholine. SomeÂ bacteria can turn choline (and also carnitine) into trimethylamine N-oxide (TMAO), high levels of which predict cardiovascular disease in humans. TMAO in turn seems to alter how inflammatory cells take up cholesterol and lipids.
Researchers at Emory arrived at choline metabolites and their connection to atherosclerosis by another route. Hanjoong Jo and his colleagues have been productively probing the mechanisms of atherosclerosis with an animal model. Very briefly: inducing disturbed blood flow in mice, in combination with a high fat diet, can result in atherosclerotic plaque formation within a few weeks. Joâ€™s team has used this model to examine changes in gene activation, microRNAs, DNA methylation, and now, metabolic markers.
McElroy’s team’s findings attracted notice because their results suggest that Ebola virus disease may affect children differently and thus, children may benefit from different treatment regimens than those for adults. The authors write that early intervention to prevent injury to the lining of blood vessels — using statins, possibly — might be a therapeutic strategy in pediatric patients. Read more
College football players tend to have stiffer arteries than other college students, even before their college athletic careers have started, cardiology researchers have found.
Although football players had lower blood pressure in the pre-season than a control group of undergraduates, stiffer arteries could potentially predict playersâ€™ future high blood pressure, a risk factor for stroke and heart disease later in life.
Researchers studied 50 freshman American-style football players from two Division I programs, Georgia Tech and Harvard, in the pre-season and compared them with 50 healthy Emory undergraduates, who were selected to roughly match their counterparts in age and race. The research is part of a longer ongoing study of cardiovascular health in Georgia Tech college football players.
The results were presented Saturday at the American College of Cardiology meeting in Washington DC, by cardiology research fellow Jonathan Kim, MD. Kim worked with Arshed Quyyumi, MD, director of Emoryâ€™s Clinical Cardiovascular Research Institute, Aaron Baggish, MD, associate director of the Cardiovascular Performance Program at Massachusetts General Hospital, and their colleagues.
â€œItâ€™s remarkable that these vascular differences are apparent in the pre-season, when the players are essentially coming out of high school,â€ says Kim. â€œWe aim to gain additional insight by following their progress during the season.â€
Despite being physically active and capable, more than half of college football players were previously found to develop hypertension by the end of their first season. Professional football players also tend to have higher blood pressure, even though other risk factors such as cholesterol and blood sugar look good, studies have found. Researchers have previously proposed that the intense stop-and-start nature of football as well as the physical demands of competitive participation, such as rapid weight gain, could play roles in making football distinctive in its effects on cardiovascular health.
In the current study, the control undergraduates had higher systolic and diastolic blood pressure than the football players: (football players: 111/63; control: 118/72). However, the football players displayed significantly higher pulse wave velocity, a measure of arterial stiffness (football: 6.5 vs control: 5.7). Pulse wave velocity is measured by noninvasive devices that track the speed of blood flow by calculating differences between arteries in the neck and the leg.
â€œIt is known that in other populations, increased pulse wave velocity precedes the development of hypertension,â€ Kim says. â€œWe plan to test this relationship for football players.â€
The football players were markedly taller and larger than the control group (187 vs 178 centimeters in height, body mass index 29.2 vs 23.7). The football players also reported participating in more hours of weight-training per week than the control group (5.4 vs 2.6).
Poring over the abundance of information presented at major scientific meetings is like trying to drink from a firehose.Â Imposing an Emory-centric filter on this year’s American Heart Association Scientific Sessions meeting in Los Angeles, here are three highlights, with a shoutout to the AHA journal Circulation, which provides a database of meeting abstracts.
Presenter Rebecca Levit, MD, a postdoc in cardiology division chair W. Robert Taylorâ€™s laboratory, was a finalist for an Early Career Investigator Award.
Â Stem cell therapies for myocardial repair have shown promise in preclinical trials, but lower than expected retention and viability of transplanted cells. In an effort to improve this, we employed an alginate encapsulation strategy for human mesenchymal stem cells (hMSCs) and attached them to the heart with a biocompatible PEG hydrogel patch in a rat MI model. Encapsulation allows for diffusion of pro-angiogenic cytokines and growth factors made by the hMSCs while maintaining them at the site of implantationâ€¦Alginate encapsulated hMSCs attached to the heart with a hydrogel patch resulted in a highly significant improvement in left ventricular function after acute myocardial infarction. The mechanism for this markedly enhanced effect appears to be increased cell survival and retention.
Â Note: alginate already has a wide variety of uses, for example in culinary arts and to make dental impressions.
suPAR, a biomarker connected with depression, inflammation and cardiovascular outcomes. Step back, C-reactive protein
A study probing myocardial ischemia (a lack of blood flow to the heart) induced by psychological stress, described in this Emory Public Health article. The presentation by Ronnie Ramadan examines physiological responses to a public speaking test as a way of predicting more severe problems.
Biomarkers circulating in the bloodstream may serve as a predictive window for recurrent stroke risk and also help doctors accurately assess what is happening in the brains of patients with acute traumatic brain injury (TBI).
Michael Frankel, MD
Researchers at Emory University School of Medicine, led by principal investigator Michael Frankel, MD, Emory professor of neurology and director of Grady Memorial Hospitalâ€™s Marcus Stroke & Neuroscience Center, are studying biomarkers as part of two ancillary studies of blood samples using two grants from the National Institutes of Health.
In the $1.47 million, four-year grant called â€œBiomarkers of Ischemic Outcomes in Intracranial Stenosisâ€ (BIOSIS), Emory researchers are analyzing blood samples from 451 patients from around the country who were enrolled in a study known as SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis), the first randomized, multicenter clinical trial designed to test whether stenting intracranial arteries would prevent recurrent stroke.
Researchers in the SAMMPRIS study recently published their results in the New England Journal of Medicine, showing that medical management was more effective than stenting in preventing recurrent strokes in these patients. Frankel’s BIOSIS research team is using blood samples from these same patients to continue learning more about the molecular biology of stroke to predict risk of a stroke occurring in the future.
â€œOur goal is to learn more about stroke by studying proteins and cells in the blood that reflect the severity of disease in arteries that leads to stroke. If we can test blood samples for proteins and cells that put patients at high risk for stroke, we can better tailor treatment for those patients,â€ says Frankel.
Patients with narrowed brain arteries, known as intracranial stenosis, have a particularly high risk of disease leading to stroke. At least one in four of the 795,000 Americans who have a stroke each year will have another stroke within their lifetime. Within five years ofÂ a firstÂ stroke,Â the risk for another stroke can increase more than 40 percent. Recurrent strokes often have a higher rate of death and disability because parts of the brain already injured by the original stroke may not be as resilient.
The other study, â€œBiomarkers of Injury and Outcome in ProTECT IIIâ€ (BIO-ProTECT)” is a $2.6 million, five-year NIH grant in which Frankelâ€™s team will use blood to determine what is happening in the brain of patients with acute TBI.Â The blood samples are from patients enrolled in the multicenter clinical trial ProTECT III (Progesterone for Traumatic brain injury, Experimental Clinical Treatment), led by Emory Emergency Medicine Professor, David Wright, MD, to assesses the use of progesterone to treat TBI in 1,140 patients at 17 centers nationwide.
In the BIO-ProTECT study, Emory is collaborating with the Medical University of South Carolina, the University of Pittsburgh, the University of Michigan and Banyan Biomarkers.
TBI is the leading cause of death and disability among young adults in the US and worldwide. According to the Centers for Disease Control and Prevention, approximately 1.4 million Americans sustain a traumatic brain injury each year, leading to 275,000 hospitalizations, 80,000 disabilities, and 52,000 deaths.
Acute TBI leads to a cascade of cellular events set in motion by the initial injury that ultimately lead to cerebral edema (swelling of the brain), cellular disruption and sometimes death. Tissue breakdown leads to the release of proteins into the bloodstream. These proteins may serve as useful biomarkers of the severity of the injury and perhaps provide useful information about response to treatment.
Using the large patient group in the ProTECT III trial, the researchers hope to validate promising TBI biomarkers as predictors of clinical outcome and also evaluate the relationship between progesterone treatment, biomarker levels and outcome.
â€œIf we can better determine the amount of brain injury with blood samples, we can use blood to help doctors better assess prognosis for recovery, and, hopefully whether a patient will respond to treatment with progesterone,â€ says Frankel.