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| Understanding why lung cancer spreads MIT biologists pinpoint a genetic change that helps tumors move to other parts of the body. CAMBRIDGE, Mass. — MIT cancer biologists have identified a genetic change that makes lung tumors more likely to spread to other parts of the body. The findings, published in the April 6 online issue of Nature, offers new insight into how lung cancers metastasize and could help identify drug targets to combat metastatic tumors, which account for 90 percent of cancer deaths.
The researchers, led by Tyler Jacks, director of the David H. Koch Institute for Integrative Cancer Research at MIT, found the alteration while studying a mouse model of lung cancer. They then compared their mouse data to genetic profiles of human lung tumors and found that reduced activity of the same gene, NKX2-1, is associated with higher death rates for lung-cancer patients.
This study represents an important step in understanding how changes that disable this gene would make tumors more aggressive, says Monte Winslow, a senior postdoctoral associate in Jacks’ lab and lead author of the paper.
Understanding the role of NKX2-1 may help scientists pursue drugs that could counteract its loss. Right now, “the sad reality is that if you could tell a patient whether their cancer has turned down this gene, you would know they will have a worse outcome, but it wouldn’t change the treatment,” Winslow says.
Winslow and his colleagues at the Koch Institute studied mice that are genetically programmed to develop lung tumors. The mice’s lung cells can be induced to express an activated form of the cancer-causing gene Kras, and the tumor suppressor gene p53 is deleted. While all of those mice develop lung tumors, only a subset of those tumors metastasizes, suggesting that additional changes are required for the cancer to spread.
The researchers analyzed the genomes of metastatic and non-metastatic tumors in hopes of finding some genetic differences that would account for the discrepancy. The absence of NKX2-1 activity in metastatic tumors was the most striking difference, Winslow says.
The NKX2-1 gene codes for a transcription factor — a protein that controls expression of other genes. Its normal function is to control development of the lung, as well as the thyroid and some parts of the brain. When cancerous cells turn down the expression of the gene, they appear to revert to an immature state and gain the ability to detach from the lungs and spread through the body, seeding new tumors.
Once the researchers identified NKX2-1 as a gene important to metastasis, they started to look into the effects of the genes that it regulates. They zeroed in on a gene called HMGA2, which had been previously implicated in other types of cancer. It appears that NKX2-1 represses HMGA2 in adult tissues. When NKX2-1 is shut off in cancer cells, HMGA2 turns back on and helps the tumor to become more aggressive.
They also found that human tumors with NKX2-1 missing and HMGA turned on tended to be metastatic, though not all metastatic tumors fit that profile.
Other researchers have reported that in about 10 percent of lung cancers, there are too many copies of NKX2-1 — the opposite of what the MIT team found in this study. That is not uncommon, says David Mu, an associate professor of pathology at Penn State University, who also studies lung cancer.
“Many cancer genes exhibit this kind of dual personality,” says Mu, who was not involved in this study. “It’s important to figure out what’s happening in different contexts.”
It would be difficult to target NKX2-1 with a drug because it’s much harder to develop drugs that turn a gene back on than shut it off, Winslow noted. A more promising possibility is targeting HMGA2 or other genes that NKX2-1 represses.
Jacks’ lab is now looking at other types of cancer, to see if NKX2-1 or HMGA2 have the same role in other metastatic cancers. “It’s great to find something that’s important in lung cancer metastasis, but it would be even better if it controlled metastasis in even a subset of other cancer types,” Winslow says.
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| Gene linked to aging also linked to Alzheimer’s CAMBRIDGE, Mass. — MIT biologists report that they have discovered the first link between the amyloid plaques that form in the brains of Alzheimer’s patients and a gene previously implicated in the aging process, SIRT1. The researchers found that SIRT1 appears to control production of the devastating protein fragments, termed A-beta peptides, that make up amyloid plaques. They also showed that in mice engineered to develop Alzheimer’s plaques and symptoms, learning and memory deficits were improved when SIRT1 was overproduced in the brain, and exacerbated when SIRT1 was deleted. The results, reported in the July 23 issue of the journal Cell, indicate that drugs that activate SIRT1 could be a promising strategy to combat Alzheimer’s, says Leonard Guarente, the MIT biology professor who led the study. Alzheimer’s disease is a neurodegenerative disorder that affects up to one-third of people who reach the age of 80. Patients suffer from memory loss and other cognitive impairments believed to be the result of damage from amyloid plaques. Amyloid plaques form when proteins called amyloid precursor proteins (APPs) are broken into smaller amyloid peptides. However, APPs can also be cleaved into harmless protein fragments. In this study, the MIT researchers showed that SIRT1 activates the production of an enzyme that cleaves APPs into harmless fragments instead of the Alzheimer’s-associated amyloid peptides. Mice engineered to produce excess SIRT1 had reduced peptide levels, while mice with SIRT1 knocked out showed increased peptide levels. The SIRT1 gene, which produces proteins called sirtuins, has previously been shown to regulate many cell activities, especially those involved in stress response and calorie deprivation. Guarente first drew attention to sirtuins about 15 years ago when he discovered that the yeast version of the gene, SIR2, regulates longevity in yeast. Later work revealed similar effects in worms, mice and rats. Other authors of the Cell paper are MIT postdoctoral associates Gizem Donmez and Dena Cohen and junior Diana Wang. | | New device for patients to monitor blood glucose levels CAMBRIDGE, Mass. — People with type 1 diabetes must keep a careful eye on their blood glucose levels: Too much sugar can damage organs, while too little deprives the body of necessary fuel. Most patients must prick their fingers several times a day to draw blood for testing.
To minimize that pain and inconvenience, researchers at MIT’s Spectroscopy Laboratory are working on a noninvasive way to measure blood glucose levels using light.
First envisioned by Michael Feld, the late MIT professor of physics and former director of the Spectroscopy Laboratory, the technique uses Raman spectroscopy, a method that identifies chemical compounds based on the frequency of vibrations of the bonds holding the molecule together. The technique can reveal glucose levels by simply scanning a patient’s arm or finger with near-infrared light, eliminating the need to draw blood.
Spectroscopy Lab graduate students Ishan Barman and Chae-Ryon Kong are developing a small Raman spectroscopy machine, about the size of a laptop computer, that could be used in a doctor’s office or a patient’s home. Such a device could one day help some of the nearly 1 million people in the United States, and millions more around the world, who suffer from type 1 diabetes.
Researchers in the Spectroscopy Lab have been developing this technology for about 15 years. One of the major obstacles they have faced is that near-infrared light penetrates only about half a millimeter below the skin, so it measures the amount of glucose in the fluid that bathes skin cells (known as interstitial fluid), not the amount in the blood. To overcome this, the team came up with an algorithm that relates the two concentrations, allowing them to predict blood glucose levels from the glucose concentration in interstitial fluid.
However, this calibration becomes more difficult immediately after the patient eats or drinks something sugary, because blood glucose soars rapidly, while it takes five to 10 minutes to see a corresponding surge in the interstitial fluid glucose levels. Therefore, interstitial fluid measurements do not give an accurate picture of what’s happening in the bloodstream.
| | Adding face shields to helmets could help avoid blast-induced brain injuries CAMBRIDGE, Mass. — More than half of all combat-related injuries sustained by U.S. troops are the result of explosions, and many of those involve injuries to the head. According to the U.S. Department of Defense, about 130,000 U.S. service members deployed in Iraq and Afghanistan have sustained traumatic brain injuries — ranging from concussion to long-term brain damage and death — as a result of an explosion. Raul Radovitzky, an associate professor in MIT’s Department of Aeronautics and Astronautics, is among the researchers looking at ways to prevent these injuries. In a paper published Monday in the Proceedings of the National Academy of Sciences, he and his colleagues report that adding a face shield to the standard-issue helmet worn by the vast majority of U.S. ground troops could significantly reduce traumatic brain injury, or TBI. The extra protection offered by such a shield is critical, the researchers say, because the face is the main pathway through which pressure waves from an explosion are transmitted to the brain. In assessing the problem, Radovitzky, who is also the associate director of MIT’s Institute for Soldier Nanotechnologies (ISN), and his research team members recognized that very little was known about how blast waves interact with brain tissue or how protective gear affects the brain’s response to such blasts. So they created computer models to simulate explosions and their effects on brain tissue. The models integrate with unprecedented detail the anatomical features of the head, including the skull, sinuses, cerebrospinal fluid and layers of gray and white matter, as well as the physical characteristics of the blast wave. To create the models, Radovitzky and his students collaborated with David Moore, a neurologist at the Defense and Veterans Brain Injury Center at Walter Reed Army Medical Center, who used magnetic resonance imaging to model features of the head. The researchers then added data collected from colleagues’ studies of how the brain tissue of pigs responds to mechanical events, such as shocks. They also included details about the explosion that creates the blast wave upon detonation, including the explosive type, mass and location relative to the target. F or more click here | |
| Helping the heart help itself Research points to new use for stem cells  Human trials of stem cell therapy for post-heart attack patients have raised as many questions as they have answered — because while the patients have tended to show some improvement in heart function, the stem cells do not appear to turn into heart cells or even survive.
But in a featured paper published in the latest edition of the journal Cell Stem Cell, Harvard Stem Cell Institute (HSCI) researchers at Brigham and Women’s Hospital (BWH) provide a solution to the puzzle — and what appears to be a new use for stem cells. The stem cells being transfused into the patients may not be developing into new heart muscle, but they still appear to be beneficial. Some stem cells in the bone marrow, called c-kit+ cells, appear capable of stimulating adult stem cells already present in the heart to repair the damaged tissue. What this means, in effect, is that the c-kit+ stem cells are functioning much as a drug might, stimulating the heart’s own repair mechanism. “It seems that heart muscle is being made from heart stem cells that are already there,” said Richard T. Lee, who led the new study. Lee, a Harvard Medical School professor of cardiology at BWH and leader of the HSCI Cardiovascular Disease Program, notes that “there have been some adult stem cells found in the heart, but it hasn’t been clear under what circumstances they are active, and how to turn them on. “The study explains why some forms of cell therapy are helping the heart even though the cells themselves don’t survive inside the heart,” Lee said. Up to this point, researchers working in regenerative medicine have envisioned two basic roles for stem cells: They can be used as treatments, to be given to patients to directly replace lost cells and repair damage; and they can be used to model diseases in the laboratory, and serve as targets for traditional drug discovery and initial testing. The Lee paper suggests a third role for these ubiquitous cells: At least in the heart, they can apparently stimulate other stem cells to repair damaged tissue. In a heart attack, heart muscle dies, reducing the heart’s ability to pump blood throughout the body. When that damage reaches a certain point, congestive heart failure, which is as lethal as many metastatic cancers, sets in. Results thus far from studies in humans — Lee’s study was done in mice — “have shown a small improvement in heart function, but a big enough improvement so there is potential to prevent heart failure,” Lee said. Lee said that the results in the mice, which had lost about 40 percent of heart function —the equivalent of a major human heart attack — showed “much better heart function when the stem cells were delivered.” Ideally, Lee said, researchers would like to find a chemical that would, like the c-kit+ stem cells, stimulate adult cardiac cells to repair heart attack damage. | |
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