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• W2108803734 abstract "Alcohol-induced DNA damage and faulty repairs may raise the risk of certain cancers, but resveratrol could provide some relief Tony Tin, PhD, a cancer biologist at Exogen Biotechnology Inc, a startup in Berkeley, California, describes himself as a moderate to occasionally heavy social drinker when he goes out with friends on the weekends. Exogen, a spinoff of Lawrence Berkeley National Laboratory, has made its name developing a way to quantify one of the most harmful types of DNA damage: double-strand breaks. So it was only natural that Dr. Tin would conduct a month-long experiment on himself to learn how his alcohol consumption might be affecting his DNA. “I wanted to see how my damage levels changed personally,” he says. “I gave up drinking for a month and, during that month, exercised and ate very healthy food. I actually saw a dramatic decrease in my DNA damage levels.” Scientists have long linked alcohol consumption to an increased risk of certain types of cancer, such as head and neck tumors and colon cancer. However, until recently, researchers knew little about the potential mechanisms. New studies are finally filling in some of the blanks along the pathway from alcoholinduced cellular and DNA damage and faulty repairs to eventual oncogenesis. A 2013 article in the journal Alcohol found significant evidence of oxidative damage even in healthy young adults who had been drinking for only 4 or 5 years.1 The preliminary study, which began as a project for students at the Autonomous University of Nayarit in Tepic, Mexico, analyzed several biomarkers of cell damage in a small group of individuals aged 18 to 23 years whose alcohol preferences skewed heavily toward beer. On average, the subjects drank 1.5 liters of alcohol every weekend. To the researchers' surprise, tests suggested that the alcohol-consuming volunteers had incurred approximately twice as much oxidative damage in their cellular membranes as their nondrinking counterparts had. Other tests revealed more oxidative DNA damage and increased activity of the alcohol dehydrogenase enzyme, which converts alcohol molecules into the noxious breakdown product acetaldehyde, which is best known for causing DNA crosslinking damage. In addition, the drinkers had less glutathione peroxidase activity, which protects against oxidative damage. Previous studies that examined potential cellular damage from alcohol consumption had focused almost exclusively on adults who were at least 40 years old. “There was a gap, or a lack of information, about oxidative damage for younger people,” says Jesús Bernardino Velázquez-Fernández, a professor at the Autonomous University of Nayarit and coauthor of the study. He says his group was among the first to study the potential impact from 5 or fewer years of alcohol consumption among young adults. The initial results, Velázquez-Fernández says, suggest that a lack of moderation even in early alcohol consumption can lead to long-term consequences. The researchers are now hoping to validate their findings in a larger group of young adults and test other biomarkers potentially linked to cancer. Backed by a crowdfunding campaign, Exogen Biotechnology has already developed a kit called MyDNABreaks that can be sent through the mail to “citizen scientists,” who fill out a short lifestyle questionnaire, prick their fingers, and send back a few drops of carefully preserved blood. The company then quantifies their level of DNA damage via a double-strand break-associated protein called p53-binding protein 1. Exogen Biotechnology is evolving in response to 2 emerging trends and has temporarily put its initial project on hold. First, research is painting a more complicated picture of how DNA damage might be influenced by alcohol and other lifestyle, environmental, and genetic factors. Before-and-after comparisons in the same person may help to clarify the impact of social drinking and other exposures. However, using a snapshot of DNA damage to identify the most significant agents of harm in a diverse population with vastly different exposures will likely prove much more difficult. Second, more studies are focusing not only on DNA damage but also on deficient DNA repair and how one or both can heighten the risk of certain types of cancer. Beyond Exogen's first kit, the company is now developing a more informative test of an individual's capacity for DNA repair. “We take live cells and we artificially induce DNA damage,” Dr. Tin explains. “In our controlled environment, we shoot the cells with radiation, which will cause a lot of damage, and then we monitor how fast it repairs that.” Exogen is also initiating exploratory clinical trials to assess how well the test might estimate the risk of lung, prostate, and breast cancer. If the company wins regulatory approval from the US Food and Drug Administration, it has a lofty goal in mind: expanding the panel of standard laboratory tests to include a new indicator of cancer risk based on an individual's DNA repair ability. DNA repair, or a lack thereof, also figures heavily in new studies that suggest how the resveratrol compound found in red wine may help to ward off some cancers. Some important clues have come from the rare pediatric disease Fanconi anemia, which has been linked to mutations in at least 16 genes, including one involved in BRCA-associated familial breast cancer. The common link is a pathway that repairs DNA crosslinking. “Individuals who have mutations in that pathway can't fix the damage,” says Robert Sclafani, PhD, a professor of biochemistry and molecular genetics at the University of Colorado School of Medicine in Denver. “So that damage will eventually lead to genome instability and cancer.” People normally have 2 defense mechanisms against alcohol damage: they can get rid of the alcohol by metabolizing it into acetic acid, a relatively mild breakdown product, and they can fix the crosslinking damage wrought by the more harmful acetaldehyde intermediate. Approximately 30% of individuals of Asian descent have a variant of the aldehyde dehydrogenase enzyme that cannot effectively break down acetaldehyde. The metabolic deficiency causes them to flush when they consume alcohol and increases the risk of esophageal cancer. Conversely, children and adults with Fanconi anemia can break down the toxic acetaldehyde compound (also present in some food products) but cannot fix any of the DNA damage it causes. These individuals are at an especially high risk of both leukemia and head and neck cancers. Researchers have now identified a small subset of people who have defects in both pathways. “It's a double whammy,” says Dr. Sclafani. The prognosis for these patients is particularly poor. So what is the connection to resveratrol? Animal studies by Dr. Sclafani and other groups have shown that the compound can prevent cancer or lessen its impact in mice that have ingested carcinogens. “If we take those mice and we feed them resveratrol, that blunts the effect: they either get fewer tumors or they don't get tumors at all,” Dr. Sclafani says. The accumulating evidence suggests that resveratrol targets and kills cells that cannot repair their own damaged DNA, thereby preventing them from becoming cancerous.2 At the molecular level, studies have indicated that resveratrol targets the protein DNA polymerase. “What we think is going on is that resveratrol is slowing DNA replication, not stopping it,” Dr. Sclafani says. “And when you do that, we know from lots and lots of studies that the DNA replication machinery starts to back up. That produces an unusual structure in the DNA–people sometimes refer to it as a ‘chicken foot.’” He hypothesizes that the molecular structure induced by resveratrol, technically called a regressed replication fork, is normally reversible. However, in a cancer cell, extensive DNA damage causes this regressed “chicken foot” to break apart. “And once it breaks, you can't fix it,” Dr. Sclafani says. Pushed over the edge by resveratrol, a fatally damaged cell dies before it can cause any lasting damage. Several research groups are investigating the potential of high-dose res veratrol, which has been well tolerated, to help prevent colon cancer and other malignancies. If he secures funding, Dr. Sclafani hopes to examine whether the compound also protects patients with Fanconi anemia from developing head and neck cancers, or prevents other patients who have been treated for head and neck cancers from developing secondary tumors. Researchers cannot yet say whether a glass of red wine every day will help to prevent cancer, especially because resveratrol's potential benefits may be offset by alcohol. The research to date suggests that, compared with beer or liquor, red wine may be a less risky weekend indulgence." @default.
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• W2108803734 title "Assessing the aftermath of an alcohol-fueled weekend: Alcohol-induced DNA damage and faulty repairs may raise the risk of certain cancers, but resveratrol could provide some relief" @default.
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• W2108803734 doi "https://doi.org/10.1002/cncy.21613" @default.
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