New animal model for elimination of latent TB

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

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 Read more

Probing visual memory at leisure

"Anecdotally, the paradigm appears to be strikingly less distressing and frustrating to both research participants and clinical patient populations than traditional neuropsychological Read more

Cancer

Progesterone could become tool vs glioblastoma

The hormone progesterone could become part of therapy against the most aggressive form of brain cancer. High concentrations of progesterone kill glioblastoma cells and inhibit tumor growth when the tumors are implanted in mice, researchers have found.

The results were recently published in the Journal of Steroid Biochemistry and Molecular Biology.

Glioblastoma is the most common and the most aggressive form of brain cancer in adults, with average survival after diagnosis of around 15 months. Surgery, radiation and chemotherapy do prolong survival by several months, but targeted therapies, which have been effective with other forms of cancer, have not lengthened survival in patients fighting glioblastoma.

The lead author of the current paper is assistant professor of emergency medicine Fahim Atif, PhD. The findings with glioblastoma came out of Emory researchers’ work on progesterone as therapy for traumatic brain injury and more recently, stroke. Atif, Donald Stein and their colleagues have been studying progesterone for the treatment of traumatic brain injury for more than two decades, prompted by Stein’s initial observation that females recover from brain injury more readily than males. There is a similar tilt in glioblastoma as well: primary glioblastoma develops three times more frequently in males compared to females.

These results could pave the way for the use of progesterone against glioblastoma in a human clinical trial, perhaps in combination with standard-of-care therapeutic agents such as temozolomide. However, Stein says that more experiments are necessary with grafts of human tumor cells into animal brains first. His team identified a factor that may be important for clinical trial design: progesterone was not toxic to all glioblastoma cell lines, and its toxicity may depend on whether the tumor suppressor gene p53 is mutated.

Atif, Stein, and colleague Seema Yousuf found that low, physiological doses of progesterone stimulate the growth of glioblastoma tumor cells, but higher doses kill the tumor cells while remaining nontoxic for healthy cells. Similar effects have been seen with the progesterone antagonist RU486, but the authors cite evidence that progesterone is less toxic to healthy cells. Progesterone has also been found to inhibit growth of neuroblastoma cells (neuroblastoma is the most common cancer in infants), as well as breast, ovarian and colon cancers in cell culture and animal models.

 

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

Valproate: epigenetic solvent

Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.

Published in Cancer, it was a clever example of number crunching, using data from the Veterans’ Administration. If you want to know about the anticancer effects of a widely used drug, check who’s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate – OR a drug that works with a similar mechanism – might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.

However, any examination of valproate should take into account neurologist Kim Meador’s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.

There’s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.

Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.

In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.

With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from – that is, which histone deacetylase in particular is responsible – find a more specific drug, and avoid potential broad side effects.

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Hypersomnia update: beyond subject one

It’s not sleep apnea. It’s not narcolepsy. Hypersomnia is a different kind of sleep disorder. There’s even an “apples and oranges” T-shirt (see below) that makes that point.

This weekend, your correspondent attended a patient-organized Living with Hypersomnia conference. One of the main purposes of the conference was to update sufferers and supporters on the state of research at Emory and elsewhere, but there was also a lot of community building — hence the T-shirts.

The story of how sleep took over one young lawyer’s life, and how her life was then transformed by flumazenil, a scarce antidote to sleeping pills she was not taking, has received plenty of attention.

Now an increasing number of people are emerging who have a condition similar to Anna Sumner’s, and several questions need answers. Read more

Posted on by Quinn Eastman in Neuro 7 Comments

NMDA receptors: triple-quadruple axel

NMDA receptors are saddled with an unwieldy name, but they are some of the most important* signaling molecules in the brain, both for learning and memory and in neurological and psychiatric diseases.

Kasper Hansen, a postdoc from Stephen Traynelis’ lab who is establishing his own at the University of Montana, is lead author on a recent paper in Neuron, which could spur research on NMDA receptors’ pharmacological properties.

The NMDA receptors in the brain are actually mix-and-match assemblies of four subunits, and most of the time in the brain, three different proteins come together to make one receptor, the authors explain. In the laboratory, it has been easier to study simpler, more homogenous, but also more artificial constructs. Hansen and his colleagues developed a way to build replicas of the more complicated NMDA receptors found in the brain and probe their distinct responses to drugs. Read more

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Two heavy hitters in this week’s Nature

Two feature articles in Nature this week on work by Emory scientists.

One is from Virginia Hughes (Phenomena/SFARI/MATTER), delving into Kerry Ressler’s and Brian Dias’ surprising discovery in mice that sensitivity to a smell can be inherited, apparently epigenetically. Coincidentally, Ressler will be giving next week’s Dean’s Distinguished Faculty lecture (March 12, 5:30 pm at the School of Medicine).

Another is from Seattle global health writer Tom Paulson, on immunologist Bali Pulendran and using systems biology to unlock new insights into vaccine design.

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Personalized molecular medicine part 3

This is a continuation of previous posts on individualized treatment for infantile-onset epilepsy, made possible by Emory scientists Stephen Traynelis and Hongjie Yuan’s collaboration with the NIH Undiagnosed Diseases Program. A companion paper containing some clinical details was recently published in Annals of Clinical and Translational Neurology.

Memantine, which was found to be effective for this particular child, is normally used to treat symptoms of Alzheimer’s disease. He has a mutation in a gene encoding a NMDA receptor, an important signaling molecule in the brain, which hyperactivates the receptor. Treatment with memantine reduced his seizure frequency from 11 per week to three per week, and eliminated one type of seizure, myoclonic jerks. It allowed doctors to taper off conventional anticonvulsant drugs, which were having little effect anyway. His cognitive ability has remained unchanged.

The team also discovered that the compound dextromethorphan, found in many over-the-counter cough medicines, was effective in the laboratory in counteracting the effects of a GRIN2A mutation found in another patient. However, these effects were mutually exclusive, because the molecular effects of the mutations are different; memantine helps L812M, while dextromethorphan helps N615K.

Yuan and Traynelis report they have an Fake Oakleys ongoing collaboration with UDP investigators to analyze the effects of mutations in NMDA receptor genes. That means more intriguing case reports are coming, they say.

Tyler Pierson, MD, PhD, lead author of the clinical paper who is now at Cedars-Sinai Medical Center in Los Angeles, and David Adams, MD, PhD, senior staff clinician at NIH, provided some additional information on the patient in the study, shown here in a Q + A format. Read more

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Personalized molecular medicine part 2

This is a continuation of the post from last week on the early-onset epilepsy patient, whom doctors were able to devise an individualized treatment for. The treatment was based on Emory research on the molecular effects of a mutation in the patient’s GRIN2A gene, discovered through whole exome sequencing.*

For this patient, investigators were able to find the Ray Ban Baratas cause for a previously difficult to diagnose case, and then use a medication usually used for Alzheimer’s disease (memantine) to reduce his seizure frequency.

Last week, I posed the question: how often do we move from a disease-causing mutation to tailored treatment? Read more

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Souped-up method for iPS cell reprogramming

Peng Jin and collaborators led by Da-Hua Chen from the Institute of Zoology, Chinese Academy of Sciences have a new paper in Stem Cell Reports. They describe a souped-up method for producing iPS cells (induced pluripotent stem cells).

Production of iPS cells in the laboratory is becoming more widespread. Many investigators, including those at Emory, are using the technology to establish “disease in a dish” models and derive iPS cells from patient donations, turning them into tools for personalized medicine research.

Read more

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True personalized medicine: from mutation to treatment

Stephen Traynelis and Hongjie Yuan

Stephen Traynelis, PhD and Hongjie Yuan, MD, PhD

How often can doctors go from encountering a patient with a mysterious disease, to finding a mutation in a gene that causes that disease, to developing a treatment crafted for that mutation?

This is true personalized molecular medicine, but it’s quite rare.

How rare this is, I’d like to explore more, but first I should explain the basics.

At Emory, Stephen Traynelis and Hongjie Yuan have been working with Tyler Pierson, David Adams, William Gahl, Cornelius Boerkoel and doctors at the National Institutes of Health’s Undiagnosed Diseases Program (UDP) to investigate the effects of mutations in the GRIN2A gene.

Their report on the molecular effects of one such mutation, which caused early-onset epilepsy and intractable seizures in a UDP patient, was recently published in Nature Communications.

With that information in hand, UDP investigators were able to repurpose an Alzheimer’s medication as an anticonvulsant that was effective in reducing seizure frequency in that patient. [The details on that are still unpublished but coming soon.]

Read more

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Local events: complex neuro diseases, DNA repair

Just a note for Atlanta-area readers about two interesting lecture series.

One is the Suddath Symposium, a two-day event today and Friday at Georgia Tech focusing on DNA repair in human disease. This is an area that Emory is strong in: Gray Crouse, Paul Doetsch, Willian Dynan and Gang Bao are speaking (all on Friday).

Another is a series of talks from Emory investigators on http://www.raybani.com/ complex neurological diseases, being put on by the Department of Cell Biology. Four, one a week (originally), all on Wednesdays at 4 pm in Whitehead 400.

Yesterday: Peter Wenner (homeostatic mechanisms/scaling). Feb. 26: Shannon Gourley (stress hormones/distorted decision-making/depression). March 5: Andrew Escayg (sodium channels/inherited epilepsy). Kerry Ressler (fear learning/PTSD) was supposed to be last week but that was derailed by ice. So Ressler will speak  on May 21, according to organizer Victor Faundez, who chose Picasso’s Guernica as the visual theme.

 

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