A new discovery by Emory researchers in certain lung cancer patients could help improve patient outcomes before the cancer metastasizes.
The researchers in the renowned Marcus Laboratory identified that highly invasive leader cells have a specific cluster of mutations that are also found in non-small cell lung cancer patients. Leader cells play a dominant role in tumor progression, and the researchers discovered that patients with the mutations experienced poorer survival rates.
The findings mark the first leader cell mutation signature identified in patients and could prove key in teasing out high-risk patients, allowing oncologists to develop a treatment plan early on before the disease has progressed.
“It has been a lot of fun to see the research go from the basic science side inside the lab to hopefully having an actual clinical impact,” says Brian Pedro, an MD/PhD student in Emory’s Medical Scientist Training Program. “Our data suggest that if you have one or more of these mutations, then we could potentially intervene early and improve patient outcomes.”
Stopping leader cells before they metastasize has long been a goal of researchers at the Winship Cancer Institute. “That is what we strive for as researchers,” Pedro says. “We are optimistic that this could be a promising clinical tool.”
The findings were published in the American Cancer Society’s journal “Cancer.”
The researchers specifically found the novel mutation cluster on chromosome 16q and compared the survival rates of those who had the mutations with those who did not. The results showed the patients who had the mutations had poorer survival rates across all stages.
Pedro says more investigation is needed to figure out why the mutations lead to poorer outcomes. He adds that he hopes the mutation signature can prove useful for cancer types beyond lung cancer.
You can learn more from Pedro’s Tweetstorm.
In the last decade, a revolution has been taking place in structural biology, the field in which scientists produce detailed maps of how enzymes and other machines in the cell work. That revolution is being driven by cryo-electron microscopy (cryo-EM for short), which is superseding X-ray crystallography as the main data-production technique and earned a chemistry Nobel in 2017.
Just before COVID-19 sent some Emory researchers home and drove others to pivot their work toward coronavirus, Lab Land had a chance to tour the cryo-EM facility and take photos, with the help of Puneet Juneja, director of the core. Juneja demonstrated how samples are prepared for data collection — see the series of photos below.
Someone coming into the facility in the Biochemistry Connector area will notice a sign telling visitors and those passing by to stay quiet (forgot to take a photo of that!). The facility has electrical shielding and temperature/humidity controls. Also two levels of cooling are required for samples, since they are flash-frozen or “vitrified” in liquid ethane, which is in turn cooled by liquid nitrogen. The cooling needs to happen quickly so that ice crystals do not form. The massive cryo-EM equipment rests on a vibration-reduction platform; no music and no loud conversation are allowed during data collection.
One of the first structures obtained in this relatively new facility was the structure of a viral RNA polymerase, the engine behind viral replication. It wasn’t a coronavirus enzyme – it was from RSV (respiratory syncytial virus).
Still, cryo-EM is a way to visualize exactly how drugs that inhibit the SARS-CoV-2 polymerase – such as remdesivir or Emory’s own EIDD-2801 – exert their effects. Chinese researchers recently published a cryo-EM structure of the SARS-CoV-2 polymerase with remdesivir in Science. Read more
This is partly a temporary good-bye and partly an introduction to Wayne Drash.
Wayne will be filling in for Quinn Eastman, who has been the main editor of Lab Land. Wayne is a capable writer. He spent 24 years at CNN, most recently within its health unit. He won an Emmy with Sanjay Gupta for a documentary about the separation surgery of two boys conjoined at the head.
Wayne plans to continue writing about biomedical research at Emory, both COVID-19-related and not. He and Quinn are particularly interested in the efforts of Emory physicians and immunologists to develop a convalescent plasma bank and serology testing, as well as the continued progress of the DRIVE antiviral. It has been inspiring to see the Emory research community rally against COVID-19, despite huge challenges. Read more
Certain types of intestinal bacteria can help protect the liver from injuries such as alcohol or acetaminophen overdose, according to Emory scientists led by pathologist Andrew Neish and physiologist Dean Jones.
The research was published on March 25 in Cell Metabolism.
“The composition of the microbiota, because of natural variation, dysbiosis, or supplementation with probiotics, can strongly affect how the liver processes both toxins and pharmacological agents, and thus have clinical consequences on how individuals respond to such exogenous chemicals,” Neish says.
While pretreatment with bacteria is needed for the observed effect in acute liver injury, probiotics or small molecule substitutes may be useful in the treatment of chronic liver diseases, the authors suggest. There are legal experts that can help with injury cases even if it’s after a slip and fall injury.
In mice, oral administration of Lactobacillus rhamnosus or LGG could protect against liver damage brought on by alcohol or acetaminophen. Several labs had already observed a beneficial effect from LGG against liver injury, but the Emory research establishes an additional mechanism.
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The protection comes from a small molecule metabolite produced by the bacteria called 5-MIAA (5-methoxyindoleacetic acid), activating the mammalian transcription factor Nrf2. Other types of bacteria did not produce 5-MIAA or activate Nrf2. While LGG is also known to improve the barrier function of the gut and dampen inflammation, liver-specific depletion of Nrf2 prevented LGG’s beneficial effects, suggesting that this is the primary mechanism of action.
Donated blood from COVID-19 survivors could be an effective treatment in helping others fight the illness – and should be tested more broadly to see if it can “change the course of this pandemic,” two Emory pathologists say.
The idea of using a component of survivors’ donated blood, or “convalescent plasma,” is that antibodies from patients who have recovered can be used in other people to help them defend against coronavirus.
Emory pathologists John Roback, MD, PhD and Jeannette Guarner, MD, wrote about the prospects of using the donated blood in a commentary published in JAMA. Their article accompanied a small study in China of five patients on ventilators whose condition improved after they were treated with convalescent plasma.
“Deploying passive antibody therapies against the rapidly increasing number of COIVD-19 cases provides an unprecedented opportunity to perform clinical studies of the efficacy of this treatment against a viral agent,” the two wrote. “If the results of rigorously conducted investigations, such as a large-scale randomized clinical trial, demonstrate efficacy, use of this therapy also could help change the course of this pandemic.”
The patients in Shenzhen were also treated with other antiviral and antiinflammatory agents, and the study was too small to come to definite conclusions. Still, the Emory authors say, the Shenzhen study provides an example of an approach that should be tested on a larger scale. Read more
Research from Adam Marcus’ and Mala Shanmugam’s labs was published Tuesday in Nature Communications – months after we wrote an article for Winship Cancer Institute’s magazine about it. So here it is again!
At your last visit to the dentist, you may have been given a mouth rinse with the antiseptic chlorhexidine. Available over the counter, chlorhexidine is also washed over the skin to prepare someone for surgery. Winship researchers are now looking at chlorhexidine and its chemical relative alexidine for another purpose: stopping cancer metastasis.
While the researchers don’t envision using chlorhexidine mouthwash as an anti-cancer measure directly, their findings suggest ways to combine other drugs, already in clinical trials, in ways that could deplete the cells needed for metastasis.
When used as an antiseptic, chlorhexidine is basically a detergent that blasts bacteria apart, scientists think. As leads for potential anti-cancer agents, chlorhexidine and its relatives appear to have a different effect. They interfere with mitochondria, the miniature power plants in our cells. Cancer cells trying to metastasize and invade other tissues seem to need their mitochondria more—especially the cells that are leading the way. Read more
Stimulating immune cells with two cancer immunotherapies together can shrink the size of the viral “reservoir” in SIV (simian immunodeficiency virus)-infected nonhuman primates treated with antiviral drugs, Emory researchers and their colleagues have concluded. The reservoir includes immune cells that harbor virus despite potent antiviral drug treatment.
The findings, reported in Nature Medicine, have important implications for the quest to cure HIV because reservoir shrinkage has not been achieved consistently before. However, the combination treatment does not prevent or delay viral rebound once antiviral drugs are stopped. Finding an HIV cure is important because, although antiretroviral therapy can reduce the amount of circulating virus to undetectable levels, problematic issues remain such as social stigma in addition to the long-term toxicity and cost of antiretroviral drugs.
“It’s a glass-half-full situation,” says senior author Mirko Paiardini, PhD. “We concluded immune checkpoint blockade, even a very effective combination, is unlikely to achieve viral remission as a standalone treatment during antiretroviral therapy.”
He adds the approach may have greater potential if combined with other immune-stimulating agents. Or it could be deployed at a different point — when the immune system is engaged in fighting the virus, creating a target-rich environment. Other HIV/AIDS researchers have started to test those tactics, he says.
Paiardini is an associate professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. The study performed in nonhuman primates, considered the best animal model for HIV studies, was carried out in collaboration with co-authors Shari Gordon and David Favre at the University of North Carolina at Chapel Hill and GlaxoSmithKline; Katharine Bar at the University of Pennsylvania; and Jake Estes at Oregon Health & Science University. Read more
A collaboration we wrote about back in 2017, between Emory cell biology chair Gary Bassell and University of Florida neurogeneticist Eric Wang, is taking off.
The National Institute of Neurological Disorders and Stroke has awarded Bassell’s and Wang’s laboratories $2.2 million over five years to examine the neuronal function of Muscleblind-like proteins, which play key roles in myotonic dystrophy.
Gary Bassell and Eric Wang have been collaborating on myotonic dystrophy research
The classic symptom for myotonic dystrophy is having trouble releasing one’s grip on a doorknob, but it is a multi-system disorder, caused by expanded DNA triplet or quadruplet repeats. RNA from the expanded repeats is thought to bind and sequester Muscleblind-like proteins, leading to an impaired process of RNA splicing.
Bassell says the project is expected to clarify how Muscleblind-like proteins regulate RNA localization in neurons and also identify therapeutic targets. In recent years, the DM research community has been paying increasing attention to neurologic symptoms.
Antios Therapeutics is moving ahead with Phase I clinical studies in Canada and Europe of an antiviral drug aimed at hepatitis B. Antios was formed in 2018 based on technology licensed from DRIVE, the non-profit drug development company owned by Emory.
Antios is developing ATI-2173, which was designed to direct a form of the drug clevudine to the liver. Pharmasset, formed by Emory scientists and later acquired by Gilead, was previously developing clevudine against hepatitis B. Pharmasset decided to stop clinical studies of clevudine in 2009 because of reports of drug-induced myopathy from South Korea. ATI-2173 is supposed to selectively deliver the drug to the liver, potentially eliminating off-target effects.
(DRIVE is also developing an drug with activity against influenza and the new coronavirus, but hepatitis B – with a weird partly double-stranded DNA genome— is quite different from both flu and coronaviruses. It does underline DRIVE’s experience with antivirals.)
Antios recently announced that the US Patent and Trademark Office has issued a notice of allowance for a patent covering ATI-2173. A full description is available from the World Intellectual Property Organization portal.
The patent is based on research carried out at Emory by Antios CEO and co-founder Abel De La Rosa, PhD, who was previously chief scientific officer at DRIVE and Emory Institute for Drug Development, and before that, an executive at Pharmasset. Read more
Congratulations to the CureGRIN Foundation, which was recently awarded a capacity-building grant from the Chan Zuckerberg Initiative’s Rare as One Network. The Chan Zuckerberg Initiative is giving 30 patient advocacy groups such as CureGRIN $450,000 each over two years.
CureGRIN works closely with Emory pharmacologist Stephen Traynelis, who has been investigating rare genetic disorders affecting NMDA receptors, which play key roles in memory, learning and neuronal development. When NMDA receptor function is perturbed by mutations, symptoms appear in infancy or early childhood, usually including epilepsy and developmental delay.
For the grant, Traynelis is named as the lead researcher for the CureGRIN Foundation, with Tim Benke of Children’s Hospital Colorado as lead clinician. Traynelis is director of the Center for Functional Evaluation of Rare Variants, which hosted a gathering at Emory Conference Center that brought together several GRIN-oriented patient advocacy groups in September 2019.