Making cardiac progenitor cells feel at home

Does this Jello dessert call up memories? We explain the connection to the Davis lab's hydrogels that help cardiac progenitor cells stay in the heart

Rare disease diagnosis, accelerated by social media

Emory geneticists' involvement in an effort to diagnose children with a rare genetic disorder. Whole exome sequencing comes up too.

Charlotte Observer highlights Lab Land

Thanks to Amber Veverka for featuring Lab Land as part of the Charlotte Observer’s regular look at science-oriented blogs. I reproduce my responses here to add some links.

Describe the range of health science research you are covering on Lab Land – and a little bit about your intended audience.

Any intriguing idea emerging from basic or clinical biomedical research happening at Emory. The blog is aimed at people who are somewhat familiar with biological concepts, like graduate students, postdocs or science journalists.

What are some of the most exciting advances you’ve recently written about?

Here are a few!

*Neuroscientists found that a mouse can pass on a learned sensitivity to a smell to its offspring

*Cardiologists discovered that heart muscle cells in mice grow in a dramatic spurt after birth, with implications for the treatment of congenital heart defects.

*Some peoples’ brains produce something that acts like a sleeping pill, giving them hypersomnia. It’s not clear what this mysterious brain chemical is yet.

*Less invasive epilepsy surgery involving lasers; seizure control with fewer cognitive side effects

*Biomedical engineers are developing ways to prevent stem cells from being washed out of the heart Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Statins, prostate cancer and mitochondria

In honor of Fathers’ Day, we are examining a connection between two older-male-centric topics: statins and prostate cancer.

Statins are a very widely prescribed class of drugs used to lower cholesterol levels, for the purpose of preventing cardiovascular disease. In cell culture, they appear to kill prostate cancer cells, but the epidemiological evidence is murkier. Statin effects on prostate cancer incidence have been up in the air, but recent reports point to the possibility that starting statins may slow progression, after a man has been diagnosed with prostate cancer.

Winship Cancer Institute researchers have some new results that shed some light on this effect. John Petros, Rebecca Arnold and Qian Sun have found that mutations in mitochondrial DNA make prostate cancer cells resistant to cell death induced by simvastatin [Zocor, the most potent generic statin]. Sun recently presented the results at the American Urological Association meeting in Orlando.

In other forms of cancer such as breast and lung cancer, genomic profiling can determine what DNA mutations are driving cancer growth and what drugs are likely to be effective in fighting the cancer. The prostate cancer field has not reached the same point, partly because prostate cancers are not generally treated with chemotherapy until late in the game, Petros says. But potentially, information on mitochondrial mutations could guide decisions on whether to initiate statin (or another) therapy.

“This is part of our soapbox,” he says. “When we are looking at mutational effects on prostate cancer, let’s be sure to include the mitochondrial genome.”

Winship’s Carlos Moreno and his colleagues are working on the related question of biomarkers that predict prostate cancer progression, after prostatectomy surgery and potentially after just a biopsy.

Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Freezing stem cells disrupts their function

What applies to meat, vegetables and fish may also apply to cells for use in cell therapy: frozen often isn’t quite as good.

Ian Copland and colleagues from Emory’s Personalized Immunotherapy Center have a paper this week in Stem Cells Reports discussing how freezing and thawing stem cells messes them up. Specifically, it disrupts their actin cytoskeletons and impairs their ability to find their niches in the body. Culturing the cells for 48 hours after thawing does seem to correct the problem, though.

The findings have some straightforward implications for researchers planning to test cell therapies in clinical applications. The authors conclude:

Until such time as a cryopreservation and thawing procedure can yield a viable and fully functional MSC product immediately after thawing, our data support the idea of using live MSCs rather than post-thaw cryo MSCs for clinical evaluation of MSCs as an immunosuppressive agent.

Notably, the Emory Personalized Immunotherapy Center has built a process designed around offering never-frozen autologous (that is, the patient’s own) mesenchymal stem cells, as therapies for autoimmune disorders such as Crohn’s disease.

Posted on by Quinn Eastman in Immunology Leave a comment

Beyond the usual suspects among Alzheimer’s proteins

If you’ve been paying attention to Alzheimer’s disease research, you’ve probably read a lot about beta-amyloid. It’s a toxic protein fragment that dominates the plaques that appear in the brains of people with Alzheimer’s. Many experimental therapies for Alzheimer’s target beta-amyloid, but so far, they’ve not proven effective.

That could be for several reasons. Maybe those treatments started too late to make a difference. But an increasing number of Alzheimer’s researchers are starting to reconsider the field’s emphasis on amyloid. Nature News has a feature this week explaining how the spotlight is shifting to the protein ApoE, encoded by the gene whose variation is responsible for the top genetic risk factor for Alzheimer’s.

In line with this trend, Emory’s Alzheimer’s Disease Research Center recently received a five-year, $7.2 million grant to go beyond the usual suspects like beta-amyloid. Emory will lead several universities in a project to comprehensively examine proteins altered in Alzheimer’s. You’ve heard of the Cancer Genome Atlas? Think of this as the Alzheimer’s Proteome Atlas, potentially addressing the same kind of questions about which changes are the drivers and which are the passengers.

Emory’s back-to-basics proteomics approach has already yielded some scientific fruit, uncovering changes in proteins involved in RNA splicing and processing. Also, the Nature feature also has some background on a clinical trial called TOMMORROW, which Emory’s ADRC is participating in.

Posted on by Quinn Eastman in Neuro Leave a comment

Oink! — Glycan receptors for flu viruses

Pigs are natural hosts for influenza viruses that can infect humans, in particular the 2009 and, going way back, 1918 H1N1 flu strains. So to understand how influenza infections spread in the body, biochemists and virologists look at pigs.

Biochemistry chair Rick Cummings’ group has a paper in PNAS this week examining the carbohydrates or glycans on the surfaces of pig lung cells, using their “shotgun glycomics” library approach. MMG graduate student Lauren Byrd-Leotis is the first author.Piglung

“The results illustrate the repertoire of specific, endogenous N-glycans of pig lung glycoproteins for virus recognition and offer a new direction for studying endogenous glycan functions in viral pathogenesis,” the team reports.

Posted on by Quinn Eastman in Immunology Leave a comment

Thyroid makes young mouse hearts grow

The entire heart muscle in young children may hold untapped potential for regeneration, new research suggests.

For decades, scientists believed that after a child’s first few days of life, cardiac muscle cells did not divide. Instead, the assumption was that the heart could only grow by having the muscle cells become larger.

Cracks were already appearing in that theory. But new findings in mice, published May 8 in Cell, provide a dramatic counterexample — with implications for the treatment of congenital heart disorders in humans. Read more

Posted on by Quinn Eastman in Heart Leave a comment

Whole exome sequencing in IBD

Last year, pediatric gastroenterologist Subra Kugathasan gave an “old fashioned” grand rounds talk at Children’s Healthcare of Atlanta’s Egleston hospital, describing a family’s struggle with a multifaceted problem of autoimmunity.

Subra Kugathasan, MD

Now the Journal of Pediatric Gastroenterology and Nutrition paper, on how the genetic alteration underlying the family’s struggles was identified, is published. Kugathasan reports that the young man at the center of the paper is scheduled for allogeneic bone marrow transplant in the United States (but not in Atlanta) in the next couple months.

The list of troubles the members of the family had to deal with is long: gastrointestinal issues and food allergies, skin irritation, bacterial + yeast infections, and arthritis. The mother and her brother were affected to some degree, as well as all three of the kids (see tree diagram). The youngest brother is the “proband”, a geneticist’s term for starting point.

As determined by whole exome sequencing, the gene responsible is FOXP3, which controls the development of regulatory T cells. These are cells that restrain the rest of the immune system; if they aren’t functioning correctly, the immune system is at war with the rest of the body, like in this family.

The genetic variant identified was new — that’s why whole exome sequencing was necessary to find it. The authors conclude:

Supporting the utility of WES [whole exome sequencing] in familial clusters of atypical IBD [inflammatory bowel disease], this approach led to a definitive diagnosis in this case, resulting in a justifiable treatment strategy of allogeneic bone marrow transplantation, the treatment of choice for IPEX [Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome].

Bone marrow transplant is a big deal; doctors are essentially wiping out the immune system then bringing it back, with several associated risks. So the decision to go ahead is not taken lightly. In general, whether bone marrow transplant — either autologous (patient donates back to self) or allogeneic (the donor is someone else) — is appropriate as a treatment for inflammatory bowel disease is still being investigated. Here, since a genetic origin is clear and there are autoimmune effects beyond the digestive system, it becomes the treatment of choice.

Posted on by Quinn Eastman in Immunology Leave a comment

Monitoring the brain’s temperature

It’s been a little while since we had an Intriguing Image. This video illustrates a surgical technique for the treatment of medication-resistant temporal lobe epilepsy.

In this procedure, which is designed to minimize cognitive side effects, the surgeon carefully uses a laser probe to heat and ablate the regions of the brain doctors think are important for seizures. Magnetic resonance imaging allows the temperature in the brain to be precisely monitored. The video was provided by Robert Gross, MD, PhD, and accompanies an upcoming paper in the journal Neurosurgery. More discussion of this procedure here and here.

Posted on by Quinn Eastman in Neuro Leave a comment

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

Two angles on cell death

One can take two very different angles when approaching Bill Kaiser’s and Ed Mocarski’s work on RIP kinases and the mechanisms of cell death. These are: the evolutionary where-does-apoptosis-come-from angle, and the anti-inflammatory drug discovery angle.

A pair of papers published this week, one in PNAS and one in Journal of Immunology, cover both of these angles. (Also, back to back papers in Cell this week, originating from Australia and Tennessee, touch on the same topic.)

First, the evolutionary angle.

Cellular suicide can be a “scorched earth” defense mechanism against viruses. Kaiser and Mocarski have been amassing evidence that some forms of cellular suicide arose as a result of an arms race of competition with viruses. The PNAS paper is part of this line of evidence. It shows that the cell-death circuits controlled by three different genes (RIP1, RIP3 and caspase 8) apparently can be lifted cleanly out of an animal. Mice lacking all three genes not only can be born, but have well-functioning immune systems.

Apoptosis is thought to be a form of cellular suicide important for the development of all multicellular organisms. That’s why, to cell and developmental biologists, it seemed rather shocking that researchers can mutate a group of genes that drive apoptosis and other forms of cellular suicide and have adult animals emerge.

Next, the drug discovery angle.

The J. Immunol paper makes that angle clear enough. Most of the authors on this paper are from GlaxoSmithKline’s “Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area.” Here, they show that a mutation in RIP1 inactivating the kinase enzyme protects mice against severe skin and multiorgan inflammation. They conclude their abstract with: “Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.”

Note: TNF-driven inflammatory diseases include rheumatoid arthritis, inflammatory bowel diseases and psoriasis, representing a multibillion dollar market.

 

Posted on by Quinn Eastman in Immunology Leave a comment
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