Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

Model of a sticky situation

Here’s an example of how 3D printing can be applied to pediatric cardiology. It’s also an example of how Georgia Tech, Emory and Children’s Healthcare of Atlanta all work together.

Biomedical engineers used a modified form of gelatin to create a model of pulmonary arteries in newborn and adolescent patients with a complex (and serious) congenital heart defect: tetralogy of Fallot with pulmonary atresia. The model allowed the researchers to simulate surgical catheter-based intervention in vitro.

The results were recently published in Journal of the American Heart Association. Biomedical engineer Vahid Serpooshan and his lab collaborated with Sibley Heart Center pediatric cardiologist Holly Bauser-Heaton; both are part of the Children’s Heart Research and Outcomes Center.

“This is a patient-specific platform, created with state-of-the-art 3D bioprinting technology, allowing us to optimize various interventions,” Serpooshan says.

Model of an adolescent patient’s pulmonary arteries, created by 3D printing. From Tomov et al JAHA (2019) via Creative Commons

 

 

Posted on by Quinn Eastman in Heart Leave a comment

Setting the goalposts for ALS clinical trials

In the fight against a relentless neurodegenerative disease such as ALS (amyotrophic lateral sclerosis), a critical question for research is: what is the definition of success?

Emory neurologists, with advice from other experts, have created a new disability rating scale for ALS. This is a set of questions patients or their caregivers answer to gauge how much ALS is eroding someone’s ability to manage daily life. The researchers think it can become a resource for testing new treatments for ALS in clinical trials.

The research used to develop the new rating scale was published on December 30 in JAMA Neurology. The rating scale itself will be available on the Emory ALS Center web site.

ALS’s attack on motor neurons makes it progressively more difficult to accomplish tasks such as household chores, daily hygiene, and eventually speaking and eating. Some patients live a year or two after diagnosis, some live ten.

Christina Fournier, MD

“If our goal in clinical trials is to have that decline happen more slowly, how we measure it matters,” says lead author Christina Fournier, MD, assistant professor of neurology at Emory University School of Medicine and co-director of Emory’s ALS Center.

Update: see Fournier’s comments to Medscape/Reuters Health here.

The current standard outcome measure is the ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised). While widely accepted in the field, the ALSFRS-R has some uneven aspects, or nonlinear weighting, which become problems when it is used to determine drug approval.

One example: a patient’s score will decline 3 points if they change from climbing stairs normally to holding a handrail, and will decline the same amount if they change from normal dressing and hygiene to being unable to dress or perform hygiene tasks without assistance. So 3 points can represent small or large changes in their lives. Also, the ALSFRS-R can change depending on symptom management, rather than underlying biology.

To put this in perspective, the most recent drug to be approved by the FDA (edaravone) displayed an effect size of 2.5 points – and the same drug faced resistance from European regulators. According to the Wall Street Journal, about 20 drugs are in clinical testing for ALS and 5 are in the late stages of development. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Powerful opioids + kids: bad combo

New research demonstrates the dangers of having powerful opioids such as fentanyl around children and adolescents. National Poison Data System reports show that many are ingesting the drugs unintentionally, but particularly concerning is a rise in the proportion of suspected suicides.

Among children, the proportion of opioid poisonings resulting in admission to a hospital critical care unit has increased since 2005, according to an analysis by Emory and Children’s Healthcare of Atlanta doctors.

Megan Land, MD, Jocelyn Grunwell, MD, PhD and colleagues in the Division of Critical Care in the Department of Pediatrics conducted the research, which is published in the journal Clinical Toxicology.

In a December 20 broadcast, critical care fellow Land told NPR’s Rhitu Chatterjee about her encounter with a child with severe respiratory distress as a result of consuming a fentanyl patch. Grunwell has previous experience studying pediatric intensive care admissions procedures and poisonings.

Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Shout out to Behind the Microscope podcast

For podcast listeners in the Emory biomedical research community, Behind the Microscope is a must-follow. It is produced by four students in Emory’s MD/PhD program: Carey Jansen, Joe Behnke, Michael Sayegh and Bejan Saeedi. They’re focused on career issues such as mentorship and grant strategy rather than the science itself (thus, complementary to Lab Land).

In their list of interviewees so far, they lean toward their fellow “double docs.” Since starting off in October, they’ve talked with Anita Corbett, Brian Robinson, Sean Stowell, Stefi Barbian and Steven Sloan (MD/PhDs underlined). Here are the Apple and Google podcast listings; episodes are also available on platforms such as Anchor.fm.

 

 

Posted on by Quinn Eastman in Uncategorized Leave a comment

Immune outposts inside tumors predict post-surgery outcomes

The immune system establishes “forward operating bases”, or lymph node-like structures, inside the tumors of some patients with kidney and other urologic cancers, researchers at Winship Cancer Institute of Emory University have discovered.

From left to right: Carey Jansen, Nataliya Prokhnevska, Hadyn Kissick and Viraj Master

Patients with well-supported immune cells in their tumors are more likely to control their cancers’ growth for a longer time — findings that could guide treatment decisions after surgery for kidney cancer. In addition, ongoing work has found the observation is broadly applicable to many cancer types, and it could help researchers expand the dramatic but sparse benefits of cancer immunotherapy to more people.

The results were published Wednesday, Dec. 11 in Nature.

“We knew that if there are more T cells in a tumor, the patient is likely to respond better to cancer immunotherapy,” says lead author Haydn Kissick, PhD. “But we were looking at a more basic question: why do some tumors have lots of T cells in them, and others don’t?”

Kissick is assistant professor of urology and microbiology and immunology at Emory University School of Medicine, Emory Vaccine Center and Winship Cancer Institute. His lab collaborated with surgeons and oncologists at Winship to examine tumor samples removed from patients with kidney, prostate and bladder cancer.

CD8 T cells hunt down and eliminate intruders – in this case, cancer cells. In patients with high levels of CD8 T cells residing in their tumors, their immune systems appeared to be better trained to suppress cancer growth after surgery, when small numbers of cancer cells (micrometastases) may be lurking elsewhere in the body. The cancers of those who had lower levels of CD8 T cells tended to progress four times more quickly after surgery than those with higher levels.

The finding has important implications, says Viraj Master, MD, who performed most of the kidney cancer surgeries. In this situation, additional treatments are not performed unless or until kidney cancer reappears, says Master, who is Fray F. Marshall Chair and professor of urology at Emory University School of Medicine and Winship’s Director of Integrative Oncology and Survivorship.

“Even after potentially curative surgery for aggressive kidney cancers, a significant fraction of patients will experience cancer recurrence,” he says. “But with this information, we could predict more confidently that some people won’t need anything else, thus avoiding overtreatment. However, on the basis of these findings, for others who are at higher risk of recurrence, we could potentially scan at more regular intervals, and ideally, design adjuvant therapy trials.”

The findings also provide insights for scientists interested in how the immune system successfully controls some cancers, but with others, the T cells become increasingly exhausted and ineffective.

“This study may lead to new insights into why immunotherapy can be so effective in some cancer types, but rarely works in others such as prostate cancer, and may highlight a path forward for developing more effective immunotherapy treatments,” says Howard Soule, PhD, executive vice president and chief science officer for the Prostate Cancer Foundation, which supported the Winship team’s work.

Kissick and his colleagues were surprised to find “stem-like” T cells, or precursors of exhausted cells, inside tumor samples. Stem-like T cells are the ones that proliferate in response to cancer immunotherapy drugs, which can revive the immune system’s ability to fight the cancer.

Tumor sample with high level of T cell infiltration. Red = CD8, yellow = MHC class II, a sign of APCs

“Lymph nodes are like ‘home base’ for the stem-like T cells,” says Carey Jansen, an MD/PhD student who is the first author of the Nature paper. “We had expected that the stem-like cells would stay in lymphoid tissue and deploy other T cells to infiltrate and fight the cancer. But instead, the immune system seems to set up an outpost, or a forward base, inside the tumor itself.”

The researchers found that other immune cells called “antigen-presenting cells” or APCs, which are usually found within lymph nodes, can also be seen within tumors. APCs help the T cells figure out when and what to attack. Like high numbers of CD8 T cells, high numbers of APCs in tumors were also a predictor of longer progression-free survival in kidney cancer patients.

The APCs and the stem-like cells were usually together within the same “nests,” in a way that resemble how the two types of cells interact in lymph nodes. This relationship was apparent in kidney cancers and also in samples from prostate and bladder cancers.

“The question of how the stem-like cells get into a tumor was not answered, but we do think that the APCs support the stem-like cells and are necessary for their maintenance,” Kissick says. “Given that these are the cells responsive to cancer immunotherapy agents, focusing on the relationship between the APCs and the T cells within the tumors could be valuable.”

Additional co-authors include: graduate student Nataliya Prokhnevska, urology chair Martin Sanda, MD and biostatistician Yuan Liu, PhD.

The research was supported by the National Cancer Institute (R00CA197891, U01CA113913), the Prostate Cancer Foundation, Swim Across America, the James M. Cox Foundation, James C. Kennedy, the Dunwoody Country Club Senior Men’s Association and an educational grant from Adaptive Technologies.

 

 

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Hedgehog pathway outside cilia

Emory geneticist Tamara Caspary is an expert on the Hedgehog pathway, critical for brain development. In particular, she and her colleagues have been studying a gene that is part of the Hedgehog pathway called Arl13b, which is mutated in Joubert syndrome, affecting development of the cerebellum and brain stem.

The Arl13b protein was known to be enriched in primary cilia, tiny hair-like cellular structures with a signaling/navigation function in neuronal development. However Caspary’s lab, in a collaboration with Frederic Charron’s group in Montreal, has found that Arl13b can also function outside cilia: in axons and growth cones.

The Hedgehog pathway has several roles, some in specifying what embryonic cells will become, and others in terms of guiding growing axons, the scientists conclude in their new paper in Cell Reports.

“Arl13b regulates Shh [Sonic Hedgehog] signaling through two mechanisms: a cilia-associated one to specify cell fate and a cilia localization-independent one to guide axons,” they write.  A related preprint, confirming Arl13b’s extra-ciliary role in mouse development, has been posted on bioRxiv.

 

 

 

 

 

Posted on by Quinn Eastman in Neuro Leave a comment

Tracking how steroid hormone receptor proteins evolved

When thinking about the evolution of female and male, consider that the first steroid receptor proteins, which emerged about 550 million years ago, were responsive to estrogen. The ancestor of other steroid hormone receptors, responsive to hormones such as testosterone, progesterone and cortisol, emerged many millions of years later.

Blue = estrogen-responsive receptors, Orange = non-aromatized (progesterone, testosterone, cortisol) hormone-responsive

Biochemist Eric Ortlund and colleagues have a new paper in Structure that reconstructs how interactions of steroid receptor proteins evolved over time. This is a complex area to model, since the receptors change shape when they bind their respective hormones, allowing them to bring in other proteins and activate genes.

First author C. Denise Okafor, a FIRST postdoctoral fellow at Emory, will be starting a position as assistant professor at Penn State next month.

The scientists also show that a mutation in the mineralocorticoid receptor associated with severe hypertension (S810L), which makes the receptor more promiscuous, restores an ancestral interaction within the protein.

“Evolutionary substitutions rewired the networks, subsequently altering hormonal interactions and allowing steroid receptors to achieve ligand specificity over time,” the authors write.

Posted on by Quinn Eastman in Uncategorized Leave a comment

Transition to exhaustion: clues for cancer immunotherapy

Research on immune cells “exhausted” by chronic viral infection provides clues on how to refine cancer immunotherapy. The results were published Tuesday, Dec. 3 in Immunity.

Scientists at Emory Vaccine Center, led by Rafi Ahmed, PhD, have learned about exhausted CD8 T cells, based on studying mice with chronic viral infections. In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease, and display inhibitory checkpoint proteins such as PD-1 on their surfaces. PD-1 is targeted by cancer immunotherapy drugs, such as pembrolizumab and nivolumab, which allow CD8 T cells to regain their ability to attack and kill infected cells and cancers.

Those drugs are now FDA-approved for several types of cancer, yet some types of tumors do not respond to them. Studying exhausted CD8 T cells can help us understand how to better draw the immune system into action against cancer or chronic infections.

In previous research, Ahmed’s lab found that exhausted cells are not all alike, and the diversity within the exhausted T cell pool could explain variability in responses to cancer immunotherapy drugs. Specifically, they observed that a population of “stem-like” cells proliferated in response to PD-1-blocking drugs, while a more differentiated population of exhausted cells stayed inactive. The stem-like cells are responsible for maintaining the exhausted T cell population, but cannot kill virus-infected or tumor cells on their own.

The current paper defines a transitional stage in between the stem-like and truly exhausted cells. The truly exhausted cells are marked by a molecule called CD101, and are unable to migrate to sites of infection and contain lower amounts of proteins needed to kill infected or tumor cells.

“The transitional cells are not completely exhausted,” says postdoctoral fellow Will Hudson, PhD, first author of the Immunity paper. “They are still capable of proliferating and performing their ‘killer cell’ functions. In our experiments, they contribute to viral control.”

The transitional cells, lacking CD101, could be a good marker for response to PD-1 blocking drugs, Hudson says. Enhancing the proliferation or survival of these cells, or preventing their transition to lasting exhaustion, may be a novel therapeutic strategy for cancer. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Radiologists wrestle with robots – ethically

Radiologists look at and analyze images, tasks computer algorithms can do. This is fertile soil for artificial intelligence (AI) — enough so that some predict that AI will replace radiologists.

John Banja, PhD

Emory bioethicist John Banja says: don’t believe the hype. AI will generate tools radiologists will want to use, he says. But human experts will have plenty to do, including making sure that the algorithms are properly vetted and trained on appropriate data.

“We already know what a lot of the ethical issues are going to be…informed consent, privacy, data protection, ownership, all that kind of stuff,” Banja recently told Health Imaging. “What we need to do is drill down to the next level, especially the practice level.”

Banja has received a grant from the Advanced Radiology Services Foundation to support a series of podcasts with radiologists over the next two years. He will be teaming up with Emory radiologist Rich Duszak, a specialist in health policy, and Norm Beauchamp, medical dean at Michigan State.

Banja and Duszak are still planning podcast sessions and lining up interviews, but they said the first episode will be on “AI hype”, and the second will cover standard of care/medical malpractice, with future issues on FDA standards.

Duszak comments on how radiologists need to take control of the algorithms in this video.

Also, with radiology chair Carolyn Meltzer, Banja recently published a review on ethics related to radiology and AI, exploring issues such as selection bias and stretching algorithms too far. Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Opioids: crunching the Tweets

Posts on publicly available social media platforms such as Twitter contain a huge volume of information about the declared activities and transient whims of millions of people. Within this unruly pile of data, there may be clues that could help public health researchers track opioid users and issues affecting them.

Abeed Sarker from Emory’s Department of Biomedical Informatics recently published a paper in JAMA Network Open on his analysis of Twitter posts about opioid use. The paper was featured in Popular Science.

Sarker and colleagues from Penn trained a machine learning algorithm on a subset of posts about opioid use, so that the algorithm could analyze a larger body of tweets. They found that Twitter posts about opioids in Pennsylvania, classified by the algorithm, matched the rates of overdose deaths and rates of opioid use measured through national surveys. Their aim is to be able to spot patterns of overdoses faster than prescription drug monitoring programs.

“The findings suggest that automatic processing of social media data, combined with geospatial and temporal information, may provide close to real-time insights into the status and trajectory of the opioid epidemic,” the authors write.

Read more

Posted on by Quinn Eastman in Neuro Leave a comment