Quinn Eastman

One more gene between us and bird flu

We’re always in favor of stopping a massive viral pandemic, or at least knowing more about what might make one happen. So we read a recent PLOS Pathogens paper with interest. The general theme is similar to this February 2019 paper from Anice Lowen’s lab in PNAS. To paraphrase Bill Murray in Ghostbusters: birds and humans living together, mass hysteria!

Here, Emory researchers looked at the M segment of influenza virus, which appears to determine host restriction, or the ability of viruses that infect bird cells to migrate to mammals. The M segment, was important for emergence of the 2009 H1N1 pandemic flu.

One of eight influenza gene segments, the M segment encodes a protein that can interfere with cellular functions (autophagic vesicles) on which the virus relies. The new data reveal that reductions in M2 protein occurred in connection with past important adaptation events, such as when a Eurasian avian-like swine virus emerged from birds in the 1970s.

“This mechanism constitutes a novel paradigm in RNA virus host adaptation, and reveals a new species barrier for IAV, which may be highly relevant for the emergence of avian IAVs into humans,” the authors conclude. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Antibody diversity mutations come from a vast genetic library

Vaccine scientists want to nudge the immune system into producing antibodies that will protect us from infection. In doing so, they are playing with fire – in a limited way. With every healthy antibody response, a process of internal evolution takes place among B cells, the immune cells that produce antibodies. It’s called “somatic hypermutation.”

In the lymph nodes, individual B cells undergo an accelerated rate of mutation. It’s as if those B cells’ DNA were being cooked with radiation or mutagenic chemicals – but only in a few genes. Then the lymph nodes select the B cells with high-affinity antibodies.

Gordon Dale, a just-defended graduate student from Joshy Jacob’s lab in Emory Vaccine Center, has a new paper in Journal of Immunology that sheds light on how somatic hypermutation takes place in both mice and humans.

In particular, Dale and Jacob found that the mutations that occur in human and mouse antibody genes are not random. They appear to borrow information from gene segments that are leftovers from the process of assembling antibody DNA in B cells.

In a mix and match process called VDJ recombination, B cells use one of many V, D, and J segments to form their antibody genes. What Dale and Jacob were looking at occurs after the VDJ step, when B cells get stimulated as part of an immune response.

They analyzed the patterns of mutations in human and mouse antibody genes, and found that mutations tend to come together, in a way that suggests that they are being copied from leftover V segments. They call this pattern “tem Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Emory Microbiome Research Center inaugural symposium

Interest in bacteria and other creatures living on and inside us keeps climbing. On August 15 and 16, scientists from a wide array of disciplines will gather for the Emory Microbiome Research Center inaugural symposium.

On the first day, Lab Land is looking forward to hearing from several of the speakers, touching on topics stretching from insects/agricultural pathogens to neurodegenerative disease. The second day is a hands on workshop organized by instructor Anna Knight on sorting through microbiome data. The symposium will be at WHSCAB (Woodruff Health Sciences Center Auditorium). Registration before August 2 is encouraged!

Many of the projects that we highlighted four years ago, when Emory held its first microbiome symposium, have continued and gathered momentum. Guest keynotes are from Rodney Newberry from WUSTL and Gary Wu from Penn.

 

Read more

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

Mouse version of 3q29 deletion: insights into schizophrenia/ASD pathways

Scientists at Emory University School of Medicine have created a mouse model of human 3q29 deletion syndrome, which is expected to provide insights into the genetic underpinnings of both schizophrenia and autism spectrum disorder.

In 3q29 deletion syndrome, a stretch of DNA containing several genes is missing from one of a child’s chromosomes. The deletion usually occurs spontaneously rather than being inherited. Affected individuals have a higher risk of developing intellectual disability, schizophrenia, and autism spectrum disorder. 3q29 deletion is one of the strongest genetic risk factors for schizophrenia, and the Emory researchers see investigating it as a way of unraveling schizophrenia’s biological and genetic complexity.

The results were published in Molecular Psychiatry.

“We see these mice as useful tools for understanding the parts of the brain whose development is perturbed by 3q29 deletion, and how it affects males and females differently,” says Jennifer Mulle, PhD, assistant professor of human genetics. “They are also a starting point for dissecting individual genes within the 3q29 deletion.”

Working with clinicians and psychologists at Marcus Autism Center, Mulle is leading an ongoing study of 3q29 deletion’s effects in humans, and observations from the mice are expected to inform these efforts. (More about Mulle here.) Read more

Posted on by Quinn Eastman in Neuro Leave a comment

B cells off the rails early in lupus

New research on the autoimmune disease systemic lupus erythematosus (SLE) provides hints to the origins of the puzzling disorder. The results are published in Nature Immunology.

In people with SLE, their B cells – part of the immune system – are abnormally activated. That makes them produce antibodies that react against their own tissues, causing a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems.

Scientists at Emory University School of Medicine could discern that in people with SLE, signals driving expansion and activation are present at an earlier stage of B cell differentiation than previously appreciated. They identified patterns of gene activity that could be used as biomarkers for disease development.

Activation can be observed at an early stage of B cell differentiation: resting naive cells (pink ellipse). Adapted from Jenks et al Immunity (2018).

“Our data indicate a disease signature across all cell subsets, and importantly on mature resting B cells, suggesting that such cells may have been exposed to disease-inducing signals,” the authors write.

The paper reflects a collaboration between the laboratories of Jeremy Boss, PhD, chairman of microbiology and immunology, and Ignacio (Iñaki) Sanz, MD, head of the division of rheumatology in the Department of Medicine. Sanz, recipient of the 2019 Lupus Insight Prize from the Lupus Research Alliance, is director of the Lowance Center for Human Immunology and a Georgia Research Alliance Eminent Scholar. The first author is Christopher Scharer, PhD, assistant professor of microbiology and immunology.

The researchers studied blood samples from 9 African American women with SLE and 12 healthy controls. They first sorted the B cells into subsets, and then looked at the DNA in the women’s B cells, analyzing the patterns of gene activity. Sanz’s team had previously observed that people with SLE have an expansion of “activated naïve” and DN2 B cells, especially during flares, periods when their symptoms are worse. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Head to head narcolepsy/hypersomnia study

At the sleep research meeting in San Antonio this year, there were signs of an impending pharmaceutical arms race in the realm of narcolepsy.

The big fish in a small pond, Jazz Pharmaceuticals, was preparing to market its recently FDA-approved medication: Sunosi/solriamfetol. Startup Harmony Biosciences was close behind with pitolisant, already approved in Europe. On the horizon are experimental drugs designed to more precisely target the neuropeptide deficiency in people with classic narcolepsy type 1 (for narcolepsy with cataplexy: hypocretin/orexin agonists).

Amidst this commercial maneuvering, a new clinical trial is underway at Emory Sleep Center. The study compares modafinil versus amphetamines for narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH).

These are not new drugs; they are old standards, when used to treat other sleep disorders. What’s remarkable here is that they are being tested “head-to-head.” In addition, the study explicitly tracks outcomes that people with NT2 and IH often talk about: sleep inertia, or difficulty waking up and getting out of bed in the morning, and brain fog, which is difficulty thinking/concentrating/paying attention. The main outcome measure is the Epworth Sleepiness Scale, which asks how likely someone is to fall asleep during daytime situations such as reading or while stopped in traffic. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Anti-inflammatory approach suppresses cancer metastasis in animal models

An anti-inflammatory drug called ketorolac, given before surgery, can promote long-term survival in animal models of cancer metastasis, a team of scientists has found. The research suggests that flanking chemotherapy with ketorolac or similar drugs — an approach that is distinct from previous anti-inflammatory cancer prevention efforts — can unleash anti-tumor immunity.

The findings, published in Journal of Clinical Investigation, also provide a mechanistic explanation for the anti-metastatic effects of ketorolac, previously observed in human breast cancer surgery.

Medical writer Ralph Moss has a great summary of this background. A commentary accompanying the JCI paper concludes: ” If this can be translated from mouse models into the clinic, then it could revolutionize treatments.”

Vikas P. Sukhatme, MD, ScD, dean of Emory University School of Medicine, is senior author of the JCI paper. He was previously at Beth Israel Deaconess Medical Center and Harvard Medical School, with lead authors Dipak Panigrahy, MD and Allison Gartung, PhD.

“Collectively, our findings suggest a potential paradigm shift in our approach to resectable cancers,” says Sukhatme. “Clinical trials are now urgently needed to validate these animal studies.”

Most cancer-related deaths come from metastases, the spread of cancer cells from a primary tumor to surrounding tissues or distant organs. The cells that seed metastases are often in microscopic clusters – a surgeon can’t see them. Chemotherapy, typically given after or prior to surgery is aimed at eradicating these cancer cells in the hopes of preventing cancer recurrence.  However, chemotherapy can sometimes stir up inflammation, promoting metastasis.

“Cancer therapy is a double-edged sword,” says Panigrahy. “Surgery and chemotherapy can induce an inflammatory or immunosuppressive injury response that promotes dormant metastatic cells to start proliferating, leading to tumor recurrence.”

Ketorolac is an inexpensive NSAID (nonsteroidal anti-inflammatory drug). Because of concern over side effects, it is only approved by the FDA for short-term pain management “at the opioid level.” It differs from other NSAIDs in that it preferentially inhibits the enzyme COX-1, more than COX-2. Other studies of prevention of cancer recurrence have focused on COX-2 inhibitors. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

I3 Venture awards info

Emory is full of fledgling biomedical proto-companies. Some of them are actual corporations with employees, while others are ideas that need a push to get them to that point. Along with the companies highlighted by the Emory Biotech Consulting Club, Dean Sukhatme’s recent announcement of five I3 Venture research awards gives more examples of early stage research projects with commercial potential.

This is the third round of the I3 awards; the first two were Wow! (basic discovery) and Synergy II/Nexus (promoting interdisciplinary collaboration). For the five Venture awards, the Dean’s office is providing a total of $100,000. The companies will then use the momentum to seek larger amounts of funding from various sources. Lab Land is still collecting information on the projects:

 

Faculty Name Technology Relevant links
Ray Dingledine + Thota Ganesh Pyrefin EP2 receptor antagonists vs epilepsy, pain, inflammation New class of potential drugs inhibits inflammation in brain
Mark Goodman, W. Robert Taylor Microbial Medical PET imaging agent for detection of bacterial infections Spoonful of sugar helps infection detection
Carlos Moreno + Christian Larsen ResonanceDx Miniaturized rapid creatinine test for point of care use  
Edmund Waller + Taofeek Owonikoko Cambium Oncology Enhancing responsiveness of pancreatic cancer to immunotherapy The Company’s lead compound was effective in animal studies for pancreatic cancer, melanoma, leukemia and lymphoma.
Chunhui Xu TK High-throughput screening for antiarrhythmic drugs using cardiomyocytes Fetal alcohol toxicity – in a dish // Cardiac ‘disease in a dish’ models advance arrhythmia research
Posted on by Quinn Eastman in Cancer, Immunology, Neuro Leave a comment

Take heart, Goldilocks — and get more sleep

Sleeping too little or too much increases the risk of cardiovascular events and death in those with coronary artery disease, according to a new paper from Emory Clinical Cardiovascular Research Institute.

Others have observed a similar U-shaped risk curve in the general population, with respect to sleep duration. The new study, published in American Journal of Cardiology, extends the finding to people who were being evaluated for coronary artery disease.

Arshed Quyyumi, MD and colleagues analyzed data from a registry of 2846 patients undergoing cardiac catheterization at Emory. The “sweet spot” appeared to be those who report sleeping between 6.5 and 7.5 hours per night.

39 percent of patients with coronary artery disease reported that they slept fewer than 6.5 hours per night, and 35 percent slept longer than 7.5 hours. For the next few years, both groups had higher risks of all-cause mortality: elevated risk of 45 percent and 41 percent, respectively. Patients were followed for an average of 2.8 years.

The extreme ends of sleep duration both had even higher risk: people who reported less than 4.5 hours per day had almost double mortality risk (96 percent), and those more than 8.5 hours had 84 percent higher mortality risk.

Patients with short sleep durations also had higher cardiovascular mortality (48 percent), but adjusting for cardiovascular risk factors attenuated the association between long sleep duration and CV risk.

A detailed assessment of someone’s sleep can require PSG (polysomnography). In this study,  researchers were able to get information by simply asking about sleep duration.

The participants in the Emory study were simply asked: “How many hours of sleep do you usually get each night (or when you usually sleep)?” This question may not always be answered accurately, since time in bed isn’t necessarily time asleep. Still, the broad strokes show that the sleep-CV health relationship is robust.

“What is most stunning to me are that these data were collected from cardiac patients about to undergo an invasive procedure, who still reported an aspect of their sleep that was meaningful and predictive of future survival,” says Donald Bliwise, PhD, a specialist in sleep and aging research who is a co-author on the Emory study. “Often, epidemiologic studies collect data far away from a clinic setting, where anxiety is less and estimations may be sharper. We have here in this clinical study beautiful evidence that estimates made ‘from the gurney’ may be just as meaningful as those collected in the field.”

Quyyumi says if patients with heart disease are sleeping poorly, it’s important to recognize that they are at higher risk and counsel them regarding getting more sleep, as well as factors that can disrupt sleep, such as caffeine, alcohol and looking at screens late in the day.

More specific treatments may depend what is interfering with high-quality sleep in a given patient. Several conditions can lead to difficulty sleeping, such as sleep apnea, restless leg syndrome, as well as depression, all of which have been linked with heart disease. Physiologically, several mechanisms are probably exerting their effects, such as weakening circadian rhythms and sleep fragmentation with aging, and obesity/metabolic syndrome driving inflammation. Read more

Posted on by Quinn Eastman in Heart Leave a comment

Repurposing a transplant drug for bone growth

The transplant immunosuppressant drug FK506, also known as tacrolimus or Prograf, can stimulate bone formation in both cell culture and animal models. This info comes from orthopedics researcher Nick Willett, PhD and colleagues, published in International Journal of Molecular Sciences (open access).

Nick Willett, PhD

The results suggest that FK506 might be repurposed as a “stand-alone” replacement for recombinant BMP-2 (bone morphogenic protein 2). That product has been a huge commercial success for Medtronic, in the context of spinal fusion surgeries, although controversial because of cost and side effects.

BMP-2 is more potent gram for gram, but FK506 still may offer some opportunities in local delivery. From Sangadala et al (2019)

One of Willett’s co-authors is orthopedics chair Scott Boden, MD, whose lab previously developed a system to search for drugs that could enhance BMP-2. Previously, other researchers had observed that FK506 can enhance the action of BMP-2 – this makes sense because FK506’s target protein is a regulator of the BMP pathway. Willett’s team used FK506 on its own, delivered in a collagen sponge.

“That is the big finding here, that it has the potential to be used on its own without any BMP-2,” he says.

The sponge is a possible mechanism for getting the drug to tissues without having too many systemic effects. Willett’s lab is now working on refining delivery, dosing and toxicity, he says.

Willett, based at the Atlanta VA Medical Center, is in the Department of Orthopedics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. He and Sree Sangadala, PhD (first author of the IJMS paper) currently have a grant from National Center for Advancing Translational Sciences on this project.

 

 

Posted on by Quinn Eastman in Immunology Leave a comment
1 2 3 4 5 6 7 8 9 10 ... 60 61   Next »