Almost precisely a decade ago, a young Atlanta lawyer named Anna was returning to work, after being treated for an extraordinary sleep disorder. Her story has been told here at Emory and by national media outlets.
Fast forward a decade to Idiopathic Hypersomnia Awareness Week 2018 (September 3-9), organized by Hypersomnolence Australia. What this post deals with is essentially the correction of a date at the tail end of Anna’s story, but one with long-term implications Read more
Last week, Lab Land put out a Twitter poll, touching on the cognitive distortions that make it difficult to do high-quality science. Lots of people (almost 50) responded! Thank you!
We had to be vague about where all this came from, because it was before the publication of the underlying research paper. Ray Dingledine, in Emory’s Department of Pharmacology, asked us to do the Twitter poll first, to see what answers people would give. Dingledine’s Read more
As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takesÂ a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.
Leslie Kean, MD, PhD
The paper’sÂ findings have implications for making this type ofÂ transplant safer and preventing graft-versus-host disease.Â In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a newÂ oneÂ with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.
CMV is often thought of asÂ harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new TÂ cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which canÂ compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients afterÂ kidney transplant.
The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010Â (a host of Emory/Winship hematologists and immunologists are co-authors).Â This paperÂ is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more
A mutation found in most melanomas rewires cancer cellsâ€™ metabolism, making them dependent on a ketogenesis enzyme, researchers at Winship Cancer Institute of Emory University have discovered.
The V600E mutation in the gene B-raf is present in most melanomas, in some cases of colon and thyroid cancer, and in the hairy cell form of leukemia. Existing drugs such as vemurafenib target the V600E mutation — the finding points to potential alternatives or possible strategies for countering resistance.Â It may also explain why the V600E mutation in particular is so common in melanomas.
Researchers led by Jing Chen and Sumin Kang have foundÂ thatÂ by promoting ketogenesis, the V600E mutation stimulates production of a chemical, acetoacetate, which amplifies the mutation’s growth-promoting effects. (A feedback mechanism! Screech!)
Although fruit flies donâ€™t develop cancer, cancer and stem cell researchers have been learning a great deal from fruit flies â€“ in particular, mutant flies with overgrown organs that resemble hippopotamuses.
A fly gene called Hippo and its relatives in mammals normally block cell proliferation and limit organ size. When flies have mutations in Hippo or other genes (together dubbed the Hippo pathway), the resulting overgrowth distorts their tissues into hippopotamus-like bulges. See Figure 3 of this review for an example. In humans, the Hippo pathway is involved in forming embryonic stem cells, suppressing cancerous growth, and also in regenerative growth and wound healing..
Working with flies, researchers at Emory have found that the abnormal growth induced by Hippo pathway disruption depends on genes involved in responding to the steroid hormone ecdysone.
â€œEcdysone is, to some degree, the fly version of estrogen,â€ says senior author Ken Moberg, PhD, associate professor of cell biology at Emory University School of Medicine.
In fly larvae, ecdysone triggers metamorphosis, in which adult structures such as wings and eyes emerge from small compartments called imaginal discs.. Ecdysone has a chemical structure like that of estrogen, testosterone and other steroid hormones found in humans. Ecdysone is not sex-specific, but it acts with the same mechanism as other steroid hormones, diffusing into cells and binding proteins that bind DNA and regulate gene activity. Read more
Usually in PET imaging, radioactive glucose is injected into the body, and since cancer cells have a sweet tooth, they take up a lot of the radioactive tracer. But plenty of the tracer also appears in the urine, complicating prostate cancer detection efforts, since the prostate is so close to the bladder. In contrast, FACBCÂ is readily taken up by prostate cancer cells, but doesnâ€™t appear as much in urine.
Because of space considerations, we did not include David Schuster’s description of how FACBC’s utility in prostate was first discovered.Â Several years ago, heÂ and Mark Goodman had begun investigating the probe’s potential in imaging brain tumors and kidney tumors, and used it withÂ a patient with a large renal mass and many enlarged lymph nodes, as described in the radiology newsletter Aunt Minnie. Read more
The big news from the recent American Society of Clinical Oncology meeting has been largelyÂ about immunotherapy drugs, also known as checkpoint inhibitors. These drugs have been shown to be effective in prolonging life in patients with some types of cancer, such as lung cancer and melanoma, but not others, such as colorectal and prostate cancer.
Lab Land asked oncologist Bradley Carthon and immunology researcher Haydn Kissick why. Both Carthonâ€™s clinical work and Kissickâ€™s lab research on prostate cancer are featured in the new issue of Winship magazine,Â but the prostate feature just touches on checkpoint inhibitors briefly.
Carthon says the reason checkpoint inhibitors havenâ€™t moved the needle with prostate cancer is â€œlikely due to the absence of infiltration of the prostatic tissue by tumor-associated lymphocytes.â€
Checkpoint inhibitors are supposed to unleash the immune system, but if the immune cells arenâ€™t in contact with the cancer cells so that the drugs can spur them into action, they wonâ€™t help much. Carthon says: â€œThe answer may be to â€˜primeâ€™ the prostate with an agent, then introduce the checkpoint inhibitors.â€ Read more
The PSA (prostate specific antigen) blood test has been criticized for years for driving men to seek biopsies and then definitive treatment for slow-growing cancers that may not pose a danger.
At the recent AUA meeting in New Orleans, urologist Martin Sanda presented results from research on tests that could allow the urology field to move beyond the PSA test as it is now. Winship magazine’s cover storyÂ has more on this topic.
Martin Sanda, MD is director of Winship Cancer Instituteâ€™s Prostate Cancer Program and chair of urology at Emory University School of Medicine
Right now, only about a sixth of men who have a biopsy based on the results of a PSA test have something that doctors agree should be called a cancer (a tumor with a Gleason score of seven or higher).
A paper published Tuesday in Nature Communications from researchers at the University of Chicago shows that honokiol inhibits the mitochondrial enzyme Sirt3, which has connections to longevity.Â Manesh Gupta and colleagues demonstrate thatÂ honokiol canÂ blockÂ cardiac hypertrophy in mice, a finding with possible relevance for the treatment of heart failure.
Sirt3 has been linked both genetically to human life span, and until now, the only way to increase levels of Sirt3 was old-fashioned calorie restriction and/or endurance exercise.
The authors write: It is believed thatÂ Sirt3 does not play a role inÂ embryonic development, but rather it fine tunes the activity ofÂ mitochondrial substrates by lysine deacetylation to protect cellsÂ from stress…Â To theÂ best of our knowledge, this is the first report describing aÂ pharmacological activator of Sirt3.
Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.
The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cellsÂ in vitro, but provides information on how to dose imatinib for new clinical applications.
â€œWe think that low doses of imatinib are mimicking â€˜emergency hematopoiesis,â€™ a normal early response to infection,â€ says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.
Imatinib, is an example of a â€œtargeted therapyâ€ against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.
Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens â€“ both bacteria and viruses â€“ exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, includingÂ tuberculosis bacteriaÂ andÂ Ebola virus. Read more
MicroRNAs have emerged as important master regulators in cells, since each one can shut down several target genes. Riding on top of the master regulators is Drosha, the RNA-cutting enzyme that initiates microRNA processing in the nucleus. Drosha and its relative Dicer have been attracting attention in cancer biology, because they are thought to beÂ behind a phenomenon where cancerous cells can â€œinfectâ€ their healthy neighbors via tiny membrane-clothed packets called exosomes.
At Emory, pharmacologist Zixu Mao and colleagues recently published in Molecular Cell their findings that Drosha is regulated by stress (experimentally: heat or peroxide) through p38 MAP kinase.
Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.
Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.
Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.
The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didnâ€™t develop tumors any faster than normal, and they didnâ€™t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1â€™s role in regulating blood vessel growth. What they did have was problems with spatial memory.