Two items relevant to long COVID

One of the tricky issues in studying in long COVID is: how widely do researchers cast their net? Initial reports acknowledged that people who were hospitalized and in intensive care may take a while to get back on their feet. But the number of people who had SARS-CoV-2 infections and were NOT hospitalized, yet experienced lingering symptoms, may be greater. A recent report from the United Kingdom, published in PLOS Medicine, studied more than Read more

All your environmental chemicals belong in the exposome

Emory team wanted to develop a standard low-volume approach that would avoid multiple processing steps, which can lead to loss of material, variable recovery, and the potential for Read more

Signature of success for an HIV vaccine?

Efforts to produce a vaccine against HIV/AIDS have been sustained for more than a decade by a single, modest success: the RV144 clinical trial in Thailand, whose results were reported in 2009. Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful. The researchers think that this signature, Read more

precision medicine

Precision medicine with multiple myeloma

“Precision medicine” is an anti-cancer treatment strategy in which doctors use genetic or other tests to identify vulnerabilities in an individual’s cancer subtype.

Winship Cancer Institute researchers have been figuring out how to apply this strategy to multiple myeloma, with respect to one promising drug called venetoclax, in a way that can benefit the most patients.

Known commercially as Venclexta, venetoclax is already FDA-approved for some forms of leukemia and lymphoma. Researchers had observed that multiple myeloma cells with one type of chromosomal DNA rearrangement tend to be sensitive to venetoclax. About 20 percent of multiple myelomas carry this rearrangement, called t(11;14).

“One of our main goals is to identify a better biomarker to predict patient response to venetoclax,” says Winship researcher Vikas Gupta, lead author of a paper published in Blood earlier this year.

Vikas Gupta, MD, PhD

Gupta works together with Winship hematologist Jonathan Kaufman and researcher Larry Boise, also associate director for education and training, to translate insights about myeloma cells into advances for patient care.

In a recent clinical trial led by Kaufman, a sizable fraction of people whose myelomas carried the t(11;14) rearrangement responded well to venetoclax, when their cancers were already refractory to other drugs. Another study that did not separate out myelomas with t(11;14) extended progression-free survival by almost a year.

However, venetoclax also was associated with increased mortality from infections, which led the FDA in 2019 to put the second study on hold temporarily. Other ongoing studies of venetoclax with multiple myeloma were affected.  It highlights the need to predict which patients would benefit from venetoclax – and which would not be likely to, for whom the drug may pose more risk.

In their paper, Winship investigators discovered that a set of cell markers predicted sensitivity to venetoclax better than t(11;14). These were markers for B cells, a type of white blood cell related to both multiple myeloma and some of the other forms of leukemia and lymphoma venetoclax is used to treat.

Gupta says that it was already possible to obtain myeloma cells from patients and test whether they are sensitive to venetoclax directly in the laboratory. But this isn’t practical for most clinics in cancer centers elsewhere.

“In contrast, the B cell phenotype can easily be assessed by flow cytometry, a technique that is routinely performed in clinical labs,” Gupta says. “So we are attempting to refine and validate our panel of flow cytometry markers, so that it can be used to easily and accurately predict which patients are sensitive to venetoclax.”

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Posted on by Quinn Eastman in Cancer Leave a comment

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!

Posted on by Quinn Eastman in Heart Leave a comment

Deep dive into NMDA receptor variation

The study of human genetics has often focused on mutations that cause disease. When it comes to genetic variations in healthy people, scientists knew they were out there, but didn’t have a full picture of their extent. That is changing with the emergence of resources such as the Exome Aggregation Consortium or ExAC, which combines sequences for the protein-coding parts of the genome from more than 60,000 people into a database that continues to expand.

ajhg-fig-2-092016

Rare mutations in the NMDA receptor genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). Shown in blue are agonist binding domains of the receptors, where several disease-causing mutations can be found.

At Emory, the labs of Stephen Traynelis and Hongjie Yuan have published an analysis of ExAC data, focusing on the genes encoding two NMDA receptor subunits, GRIN2A and GRIN2B. These receptors are central to signaling between brain cells, and rare mutations in the corresponding genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). GRIN2B mutations have also been linked with autism spectrum disorder.

steveandhongjie

Steve Traynelis and Hongjie Yuan

The new paper in the American Journal of Human Genetics makes a deep dive into ExAC data to explore the link between normal variation in the healthy population and regions of the proteins that harbor disease-causing mutations.

In addition, the paper provides a detailed look at how 25 mutations that were identified in individuals with neurologic disease actually affect the receptors. For some patients, this insight could potentially guide anticonvulsant treatment with a repurposed Alzheimer’s medication. Also included are three new mutations from patients identified by whole exome sequencing, one in GRIN2A and two in GRIN2B.

“This is one of the first analyses like this, where we’re mapping the spectrum of variation in a gene onto the structure of the corresponding protein,” says Traynelis, PhD, professor of pharmacology at Emory University School of Medicine. “We’re able to see that the disease mutations cluster where variation among the healthy population disappears.”

Heat map of agonist binding domain for GRIN2A.

Heat map of agonist binding domain for GRIN2A. From Swanger et al AJHG (2016).

Postdoctoral fellow Sharon Swanger, PhD is first author of the paper, and Yuan, MD, PhD, assistant professor of pharmacology, is co-senior author.

It’s not always obvious, looking at the sequence of a given mutation, how it’s going to affect NMDA receptor function. Only introducing the altered gene into cells and studying protein function in the lab provides that information, Traynelis says.

NMDA receptors are complicated machines: mutations can affect how well they bind their ligands (glutamate and glycine), how they open and shut, or how they are processed onto the cell surface. On top of that complexity, mutations that make the receptors either stronger or weaker can both lead the brain into difficulty; within each gene, both types of mutation are associated with similar disorders. With some GRIN2A mutations, the functional changes identified in the lab were quite strong, but the effect on the brain was less dramatic (mild intellectual disability or speech disorder), suggesting that other genetic factors contribute to outcomes.

Clinical relevance

Traynelis and Yuan previously collaborated with the NIH’s Undiagnosed Disease Program to show that the Alzheimer’s medication memantine can be repurposed as an anticonvulsant, for a child with intractable epilepsy coming from a mutation in the GRIN2A gene. (Nature Communications, Annals of Clinical and Translational Neurology)

Memantine is an NMDA receptor antagonist, aimed at counteracting the overactivation of the receptor caused by the mutation. Memantine has also been used to treat children with epilepsy associated with mutations in the related GRIN2D gene. However, memantine doesn’t work on all activating mutations, and could have effects on the unmutated NMDA receptors in the brain as well. Traynelis reports that his clinical colleagues are developing guidelines for physicians on the use of memantine for children with GRIN gene mutations.

This study and related investigations were supported by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD082373), the National Institute of Neurological Disorders and Stroke (R24NS092989), the Atlanta Clinical & Translational Science Institute (UL1TR000454), and CURE Epilepsy: Citizens United for Research in Epilepsy.

 

Posted on by Quinn Eastman in Neuro 2 Comments

Cancer metastasis: isolating invasive cells with a color change

The capacity of cancer cells to spread throughout the body and metastasize (invade new tissues) makes them deadly. What makes metastatic cells different?

Scientists at Winship Cancer Institute of Emory University have developed a technique for isolating individual cells that display invasive behavior out of a large group in culture by changing their color.

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Posted on by Quinn Eastman in Cancer Leave a comment