Donated blood from COVID-19 survivors could be an effective treatment in helping others fight the illness – and should be tested more broadly to see if it can “change the course of this pandemic,” two Emory pathologists say.
The idea of using a component of survivors’ donated blood, or “convalescent plasma,” is that antibodies from patients who have recovered can be used in other people to help them defend against coronavirus.
Emory pathologists John Roback, MD, Read more
Research from Adam Marcus’ and Mala Shanmugam’s labs was published Tuesday in Nature Communications – months after we wrote an article for Winship Cancer Institute’s magazine about it. So here it is again!
At your last visit to the dentist, you may have been given a mouth rinse with the antiseptic chlorhexidine. Available over the counter, chlorhexidine is also washed over the skin to prepare someone for surgery. Winship researchers are now looking at chlorhexidine Read more
Stimulating immune cells with two cancer immunotherapies together can shrink the size of the viral “reservoir” in SIV-infected nonhuman primates treated with antiviral drugs. Important implications for the quest to cure HIV, because reservoir shrinkage has not been achieved consistently Read more
This finding, published in Journal of Clinical Investigation, had clear implications for the treatment of osteoporosis in post-menopausal women. Prompted by external emails, Lab Land learned that the Emory investigators are now continuing their research in the clinic.
Endocrinologist/osteoimmunologist Roberto Pacifici and colleague Jessica Alvarez are conducting a double-blind study for women aged 50-65, using VSL3, a widely available and inexpensive dietary supplement. Participants would take the supplement or placebo for a year. More information is available here.
In mice, the loss of estrogen increases gut permeability, which allows bacterial products to activate immune cells in the intestine. In turn, immune cells release signals that break down bone. It appears that probiotics both tighten up the permeability of the gut and dampen inflammatory signals that drive the immune cells. Read more
Parents around the world can relax, knowing that their kids won’t inherit all of their stresses — at least at the DNA or epigenetic level. In an animal model, neuroscientists at Yerkes National Primate Research Center have shown they can reverse influences of parental stress by exposing parents to behavioral interventions following their own exposure to stress.
“These results in our mouse model are an important public health contribution because they provide optimism for applying similar interventional approaches in humans and breaking intergenerational cycles of stress,” says lead author Brian Dias. More information here.
The research was published in Biological Psychiatry, and is a continuation of Dias’ work with Kerry Ressler on this topic, which earned some attention in 2013. Note: the mice weren’t inheriting a fear as much as a sensitivity to a smell. Even so, it remains an intriguing example of how transgenerational (um, since the word “epigenetic” is so stretchy now) influences can be studied in a precise molecular way.
Stephanie Foster sees herself one day specializing in addiction psychiatry. When she started her MD/PhD studies at Emory, she sought out neuroscientist David Weinshenker to discuss research projects. She is now examining potential treatments for opiate addiction based on galanin, a neuropeptide found in the brain.
Weinshenker and his colleagues had already been studying galanin in relation to stimulants such as cocaine. Preliminary studies in animals indicate that activating galanin signals might reduce the rewarding effects of opiates, withdrawal symptoms, and relapse-like behavior.
“This was a whole new direction that looked promising,” Foster says. “But first, we have to work out the brain circuitry.”
Foster comes from a Native American background, and has a long-range plan to work in the Indian Health Service. The death rate of Native Americans from opiate overdoses is the highest of any American population group, according to the Centers for Disease Control and Prevention. She would like to establish a research lab in a region of the country where she could continue her addiction research and also work closely with Native communities.
Screenshot from NIH reporter (grant database). F31 grants for year 2018.
Last year, Foster applied for and received an individual grant from the National Institute on Drug Abuse to support her work. Emory currently leads U.S. universities in the number of graduate students holding their own active grants from the National Institutes of Health. This reflects a multi-year effort to build instruction in critical parts of scientific life: planning and communicating about one’s work.
With opiate addiction, convincing others that the topic is worthwhile is not so difficult. Foster notes that few treatments are available for the early stages of opiate addiction. Long-lasting opiate substitutes/replacements such as methadone and buprenorphine are used once dependence has set in, and another medication, lofexidine, was recently approved for acute withdrawal symptoms.
“There isn’t really anything for people before they reach that stage,” Foster says. “Our idea is to look for an intervention that could be given earlier.” Read more
Because circulating progenitor cells repair blood vessels, they are a measure of regenerative capacity in the cardiovascular system. Cardiologist Arshed Quyyumi, MD and his colleagues at Emory Clinical Cardiovascular Research Institute have intensively studied this cell type as a marker of vulnerability or resilience.
A recent paper from Quyyumi’s team in Circulation Research examines circulating progenitor cells (CPCs) through the lens of racial disparity. The authors find that African-Americans tend to have lower levels of this regenerative biomarker:
In a large well-characterized biracial cohort, we demonstrate that black participants had significantly lower CPC counts compared with whites, even after adjustment for differences in demographic factors and CVD risk factors. These results were validated in an independent cohort. Thus, on average, after adjustment for sex and other CVD risk factors, blacks have CPC levels that are ≈15% to 30% lower compared with whites, even in subjects free of risk factors. CPC levels decline with age, reaching on average half the levels at age 80 compared with age 20. We found that blacks have CPC counts equivalent to those in whites who are 14 years older. CPC levels are higher after AMI as a result of mobilization because of injury. We show for first time that blacks have 30% to 35% lower CPC mobilization in the setting of AMI.
Epigenetics may mean “above the genes,” but a lot of the focus in the field is on DNA methylation, a chemical modification of DNA itself. Methylation doesn’t change the actual DNA letters (A, C, G and T), but it does change how DNA is handled by the cell. Generally, it shuts genes off and is essential for cell differentiation.
The most commonly studied form of DNA methylation appears on the DNA letter C (cytosine). Drosophila, despite being a useful genetic model of development, have very little of this form of DNA methylation. What they do have is methylation on A — technically, N6-methyladenine, although little was known about what this modification did for flies.
Emory geneticists Bing Yao, PhD, Peng Jin, PhD and colleagues now have shown that an enzyme that removes methylation from A is critical for neuronal development in Drosophila.
This finding is significant because the enzyme is in the same family (TET for ten-eleven translocation) of demethylases that trigger removal of DNA methylation from C in mammals. The function of TET enzymes, revealing that cells actively removed DNA methylation rather than just letting it slough off, was discovered only in 2009. Read more
What part of the intestine is problematic matters more than inflammatory bowel disease subtype (Crohn’s disease vs ulcerative colitis), when it comes to genetic activity signatures in pediatric IBD.
Suresh Venkateswaran and Subra Kugathasan in the lab
That’s the takeaway message for a recent paper in Cellular and Molecular Gastroenterology and Hepatology (the PDF is open access) from gastroenterologist Subra Kugathasan and colleagues. His team has been studying risk factors in pediatric IBD that could predict whether a child will experience complications requiring surgery.
“This study has demonstrated that tissue samples from the ileum and rectum of CD patients show higher molecular level differences, whereas in tissue samples from two different patients with the same type of disease, the molecular differences are low,” Kugathasan says. “This was an important question to answer, since IBD can be localized to one area, and the treatment responses can vary and can be tailored to a localized area if this knowledge is well known.”
Research associate Suresh Venkateswaran, PhD, is the first author on the CMGH paper.
“We see that the differences are not connected to genomic variations,” he says. “Instead, they may be caused by non-genetic factors which are specific to each location and disease sub-type of the patient.”
These findings have implications for other study designs involving molecular profiling of IBD patients. The authors believe the findings will be important for future design of locally acting drugs.
Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works. Researchers at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors and cancer cell lines resistant to cisplatin, along with an experimental drug that targets that enzyme.
Cisplatin is a DNA-damaging agent used in standard treatment for lung, head and neck, ovarian, and testicular cancers. It has a simple structure, grabbing DNA with its metallic (platinum) arms to form crosslinks. It used to be known as “cis-flatten” because of its nausea-inducing side effects. The experimental drug, lestaurtinib, has already been tested in clinical studies in combination with other chemotherapy drugs, which means it could easily go into trials against tumors displaying cisplatin resistance.
Sumin Kang, PhD, and colleagues at Winship decided to look for enzymes whose activity was necessary for cancer cells to withstand cisplatin treatment. They chose kinases, enzymes that often control some aspect of cell growth and are have plenty of existing drugs targeting them. The researchers found that in combination with a sub-lethal amount of cisplatin, “knocking down” the activity of the kinase MAST1 kills a cell. But how does that combination work?
Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.
The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.
When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.
The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.
“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.
“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”
The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.
While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.
With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.
The term “stem cell” is increasingly stretchy. Orthopedic specialists have been using it when referring to bone marrow concentrate or platelet rich plasma, which are marketed as treatments for joint pain. At Lab Land, we have an interest in pluripotent stem cells, which can differentiate into many types of tissues.
For many applications, the stem cells are actually impurities that need to be removed, because pluripotent stem cells are capable of becoming teratomas, a type of tumor. For quality control, researchers want to figure out how to ensure that the stem-cell-derived cardiac muscle or neural progenitor or pancreas cells (or whatever) are as pure as possible.
Cardiologist and stem cell expert Chunhui Xu has been continuing a line of investigation on this topic. In a recent paper in ACS Chemical Biology, her team showed that “suicide-inducing molecules” can eliminate undifferentiated stem cells from a mixture of cells. This stem-cell-derived mixture was mostly cardiac muscle cells or their progenitors, which Xu’s team wants to use for therapeutic purposes.
Other labs have used metabolic selection – depriving cells of glucose and giving them only lactate –as a selective method for eliminating stem cells from cardiac muscle cultures. This paper shows that the “selective suicide” method works for early-stage differentiation cultures, containing cardiac progenitors, while the metabolic method works only for late-stage cultures contains beating cardiomyocytes.
Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.
The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.
Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons
The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.
“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.” Read more