More NMDA but less excitotoxicity? Now possible

Many researchers have wanted to enhance NMDA receptor signals to treat disorders such as schizophrenia. But at the same time, they need to avoid killing neurons with “excitotoxicity”, which comes from excess calcium entering the Read more

Update on pancreatic cancer: images and clinical trial

In 2018, Winship magazine had a feature story on pancreatic cancer. Our team developed an illustration that we hoped could convey the tumors’ complex structure, which contributes to making them difficult to treat. Oncologist Bassel El-Rayes described how the tumors recruit other cells to form a protective shell. "If you look at a tumor from the pancreas, you will see small nests of cells embedded in scar tissue," he says. "The cancer uses this scar Read more

New animal model for elimination of latent TB

An animal model could help researchers develop shorter courses of treatment for latent Read more

More NMDA but less excitotoxicity? Now possible

Emory pharmacologists have discovered a new class of potential drugs that might allow them to have their cake and eat it too — with reference to NMDA receptors, important control sites in the brain for learning and memory.

Many researchers have wanted to enhance NMDA receptor signals to treat disorders such as schizophrenia. But at the same time, they need to avoid killing neurons with “excitotoxicity”, which comes from excess calcium entering the cell. Excitotoxicity is thought to be a major mechanism of cell death in stroke and traumatic brain injury.

Usually more sensitivity to NMDA activation and excess calcium go hand in hand. In a new Nature Chemical Biology paper, pharmacologist Stephen Traynelis and colleagues have identified a group of compounds that allow them to separate those two aspects of NMDA signaling.

These compounds appear to selectively decrease how much calcium (as opposed to sodium) flows through the NMDA ion channel. Traynelis says that the discovery opens up pharmacological possibilities for NMDA receptors similar to those for other receptor classes that are prominent drug targets, such as G-protein coupled receptors and acetylcholine receptors. With such receptors, the drugs are called “biased agonists” or “biased modulators” because they shift the balance of how the ion channel responds.

For NMDA receptors, how these newly identified compounds work on a molecular level needs to be explored, and could lead to the long-standing goal of NMDA-based neuroprotection for treatment of stroke/TBI, the authors note. Postdoc Riley Perszyk is first author, with cell biologist Gary Bassell and chemists Dennis Liotta and Lanny Liebeskind as co-authors.

Traynelis discussed this research in his Hodgkin Huxley Katz Prize Lecture to the Physiology 2019 conference in Scotland in December 2019 (the part about the new class of NMDA modulators starts at about 20 minutes).

Posted on by Quinn Eastman in Neuro Leave a comment

Update on pancreatic cancer: images and clinical trial

In 2018, Winship magazine had a feature story on pancreatic cancer. Our team developed an illustration that we hoped could convey the tumors’ complex structure, which contributes to making them difficult to treat. Oncologist Bassel El-Rayes described how the tumors recruit other cells to form a protective shell.

“If you look at a tumor from the pancreas, you will see small nests of cells embedded in scar tissue,” he says. “The cancer uses this scar tissue as a shield, to its own advantage.”

With El-Rayes and fellow oncologist Walid Shaib, Greg Lesinski’s lab recently published a paper in JCI Insight. The point of the paper was to look at how chemotherapy changes immune activity in the tumor microenvironment, but we also get vivid images giving us a glimpse of those nests. It helps to view these images as large as possible, so please check them out at the journal’s site, which has no paywall.

Regions stained green are tumor-rich; red regions are immune cell-rich, and blue regions are rich in stromal cells (stellate/fibroblast cells). The goal is to get immune cells to envelop the tumors more, like in square 8.

The 2018 magazine story also laid out some of Lesinski’s and El-Rayes’ ideas.

Based on his lab’s recent success in animal models, Lesinski thinks that combining an immunotherapy drug with agents that stop IL-6 could pry open pancreatic cancers’ protective shells. In those experiments, the combination resulted in fewer stellate cells and more T cells in the tumors. Fortunately, a couple of “off-the-shelf” options, drugs approved for rheumatoid arthritis, already exist for targeting IL-6, Lesinski says.

On that theme, we noticed that a clinical trial was posted on clinicaltrials.gov in December that implements those proposals: “Siltuximab and Spartalizumab in Patients With Metastatic Pancreatic Cancer”. El-Rayes is the principal investigator, and it is not yet recruiting. Siltuximab is an antibody against IL-6 and spartalizumab is a second generation PD-1 inhibitor.

Posted on by Quinn Eastman in Cancer Leave a comment

New animal model for elimination of latent TB

The significance of a recent Tulane/Yerkes study on eradicating latent tuberculosis in non-human primates may not be apparent at first glance. After all, it used the same antibiotic regimen (isoniazid + rifapentine) that is recommended by the CDC for human use.

But consider whether someone who was exposed to TB in childhood might still have it in their lungs somewhere. It’s difficult to know if treatments get rid of the bacteria completely.

“The antibiotic treatment we used for this study is a new, shorter regimen the CDC recommends for treating humans with latent tuberculosis, but we did not have direct evidence for whether it completely clears latent infection,” says Yerkes/Emory Vaccine Center researcher Jyothi Rengarajan, who was co-principal investigator along with Deepak Kaushal of Tulane. “Our experimental study in macaques showing almost complete sterilization of bacteria after treatment suggests this three-month regimen sterilizes humans as well.”

In an editorial in the same journal, CDC and Johns Hopkins experts call the results “dramatic” and say application of the drug regimen “could presage a major step forward in TB prevention and control.” Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Transplant research: immune control via Fc receptors on T cells

Emory transplant researchers have identified a control mechanism the immune system uses to tamp down chronic inflammation. The findings provide insight into how some people were able to stop taking immunosuppressive drugs after kidney transplant.

In addition, they may be important for a full understanding of how many drugs for cancer and autoimmune disorders (therapeutic antibodies) work. The results were published on January 14 in Immunity.

In a twist, scientists have known about the molecules involved for a long time. They’re Fc receptors. Usually, we can think of them acting like oven mitts that immune cells use to grab onto antibodies. Fc receptors bind the constant (unvarying) portions of antibodies, which are the same no matter what they’re directed against.

Mandy Ford, PhD and graduate student Anna Morris

The news here is that an inhibitory variety of Fc receptor – FcγRIIB — is found on CD8+ T cells, and is a way of squeezing off T cell activity. Dogma over the past few decades held that T cells do not express Fc receptors, although evidence for them doing so went back to the 1970s.

“Our data suggest that the physiologic relevance of this pathway is to allow for control of active, highly differentiated effector T cells in the setting of chronic inflammation in order to limit immune pathology,” says senior author Mandy Ford, PhD, scientific director of Emory Transplant Center.

The co-first authors of the paper are IMP graduate student Anna Morris and surgical resident Clara Farley. They and their colleagues probed the functions of FcγRIIB on T cells in mice, and also found that increased expression of FcγRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. This data came from the CTOT09 study from the Clinical Trials in Organ Transplantation Consortium. Read more

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Probing visual memory at leisure

Emory Brain Health researchers have developed a computer program that passively assesses visual memory. An infrared eye tracker monitors eye movements, while the person being tested views a series of photos.

This approach, relatively unstrenuous for those whose memory is being assessed, is an alternative for the diagnosis of mild cognitive impairment or Alzheimer’s disease. It detects degeneration of the regions of the brain that govern visual memory (entorhinal cortex/hippocampus), which are some of the earliest to deteriorate.

The approach was published in Learning and Memory last year, but bioinformatics chair Gari Clifford discussed the project at a recent talk, and we felt it deserved more attention. First author Rafi Haque is a MD/PhD student in the Neuroscience program, with neurology chair/Goizueta ADRC director Allan Levey as senior author.

Eye tracking of people with MCI and Alzheimer’s shows they spend less time checking the new or missing element in the critical region of the photo, compared with healthy controls. Adapted from Haque et al 2019.

The entire test takes around 4 minutes on a standard 24 inch monitor (a follow-up publication on an iPad version is in the pipeline). Photos are presented twice a few minutes apart, and the second time, part of the photo is missing or new – see diagram above. Read more

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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

 

 

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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

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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

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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.

 

 

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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
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