Imagine a shaker table, where kids can assemble a structure out of LEGO bricks and then subject it to a simulated earthquake. Biochemists face a similar task when they are attempting to design thermostable proteins, with heat analogous to shaking. 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.
A recent publication from Bill Kaiserâ€™s and Ed Mocarskiâ€™s labs in Cell Host & Microbe touches on a concept that needs explaining: oncolytic viruses.
Viruses have been subverting the machinery of healthy cells for millions of years, and many viruses tend to infect particular tissues or cell types. So they areÂ a natural starting point for researchers to engineer oncolytic viruses, which preferentially infect and kill cancer cells.
Emory dermatologist Jack Arbiser has been investigating (andÂ recently patented) inhibitors of the enzyme Nox4 as potential anti-cancer drugs.
Nox4 has emerged as a potentialÂ therapeutic targetÂ in ataxia-telangiectasia, a rare multifaceted genetic disorder that leads to neurological problems, a weakened immune system and an increased risk of cancer. Ataxia-telangiectasia (or A-T) is caused by a defect in ATM, a sensor responsible for managing cellsâ€™ responses to DNA damage and other kinds of stress.
In a February PNAS paper, researchers at the National Cancer Institute led by William Bonner reportÂ that a Nox4 inhibitor can dial back oxidative stress and DNA damage in ataxia-telangiectasia cells, and can reduce cancer rates in a mouse model of the disease. Nox4 wasÂ activated in cells and tissue samples obtained from A-T patients.
The Nox4 inhibitor the NCI team used, fulvene-5, was originally identified by Arbiser in a 2009 Journal of Clinical Investigation paper as a possibleÂ treatment for hemangiomas, a common tumor in infants that emerges from blood vessels.
It arises from what scientists previously described as â€œjunk DNAâ€ or â€œthe dark matter of the genome,â€ but this gene is definitely not junk. The gene Gas5Â acts as a brake on steroid hormone receptors, making it a key player in diseases such as hormone-sensitive prostate and breast cancer.
Emory researchers have obtained a detailed picture of how the Gas5 RNA interacts with steroid hormone receptors. Their findings show how the Gas5 RNA takes the place of DNA, and give hints as to how it evolved.
Scientists used to think that much of the genome was â€œfly-over countryâ€: not encoding any protein and not even accessed much by the cellâ€™s gene-reading machinery. Recent studies have revealed that a large part of the genome is copied into lincRNAs (long intergenic noncoding RNAs), of which Gas5 is an example. Read more
PeopleÂ interested in drug discoveryÂ may have heard of “Lipinski’s rule of five,” a rough-and-ready set of rules for determining whether a chemical structure is going to be viable as a orally administered drug or not. TheyÂ basically say that if a compound is too big, too greasy or too complicated, it’s not going to get into the body and make it to the cells you want to affect. These guidelinesÂ have been the topic of much debate among medicinal chemists and pharmacologists.
The namesakeÂ forÂ this set of rules, Chris Lipinski, will be speakingÂ at Winship Cancer Institute Wednesday afternoonÂ (4:30 pm, Nov 5, C5012) onÂ “The Rule of 5, Public Chemistry-Biology Databases and Their Impact on Chemical Biology and Drug Discovery.” Lipinski spent most of his career at Pfizer (while there,Â he published the “rule of 5 paper“) and now is a consultant at Melior Discovery.