Now, a research team led by scientists at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT has unearthed one of the key players behind such drug resistance. Published in the Nov. 25 issue of the journal Nature, the researchers pinpoint a novel cancer gene, called “COT” (also known as MAP3K8), and uncover the signals it uses to drive melanoma. The research underscores the gene as a new potential drug target, and also lays the foundation for a generalized approach to identify the molecular underpinnings of drug resistance in many forms of cancer. “In melanoma, as well as several other cancers, there is a critical need to understand resistance mechanisms, which will enable us to be smarter up front in designing drugs that can yield more lasting clinical responses,” said senior author Levi Garraway, a medical oncologist and assistant professor at Dana-Farber and Harvard Medical School, and a senior associate member of the Broad Institute. “Our work provides an unbiased method for approaching this problem not only for melanoma, but for any tumor type.”More than half of all melanoma tumors carry changes (called “mutations”) in a critical gene called B-RAF. These changes not only alter the cells’ genetic makeup, but also render them dependent on certain growth signals. Recent tests of drugs that selectively exploit this dependency, known as RAF inhibitors, revealed that tumors are indeed susceptible to these inhibitors — at least initially. However, most tumors quickly evolve ways to resist the drug’s effects.To explore the basis of this drug resistance, Garraway and his colleagues applied a systematic approach involving hundreds of different proteins called kinases. They chose this class of proteins because of its critical roles in both normal and cancerous cell growth. Garraway’s team screened most of the known kinases in humans — roughly 600 in total — to pinpoint ones that enable drug-sensitive cells to become drug-resistant.The approach was made possible by a resource created by scientists at the Broad Institute and the Center for Cancer Systems Biology at Dana-Farber, including Jesse Boehm, William Hahn, David Hill, and Marc Vidal. The resource enables hundreds of proteins to be individually synthesized (or “expressed”) in cells and studied in parallelFrom this work, the researchers identified several intriguing proteins, but one in particular stood out: COT. Remarkably, the function of this protein had not been previously implicated in human cancers. Despite the novelty of the result, it was not entirely surprising, since COT is known to trigger the same types of signals within cells as B-RAF. (These signals act together in a cascade known as the MAP kinase pathway.)While their initial findings were noteworthy, Garraway and his co-workers sought additional proof of the role of COT in melanoma drug resistance. They analyzed human cancer cells, searching for ones that exhibit B-RAF mutations as well as elevated COT levels. The scientists successfully identified such “double positive” cells and further showed that the cells are indeed resistant to the effects of the RAF inhibitor.“These were enticing results, but the gold standard for showing that something is truly relevant is to examine samples from melanoma patients,” said Garraway.Such samples can be hard to come by. They must be collected fresh from patients both before and after drug treatment. Moreover, these pre- and post-treatment samples should be isolated not just from the same patient but also from the same tumor.Garraway and his colleagues were fortunate to obtain three such samples for analysis, thanks to their clinical collaborators led by Keith Flaherty and Jennifer Wargo at Massachusetts General Hospital. In two out of three cases, COT gene levels became elevated following RAF inhibitor treatment or the development of drug resistance. In other cases, high levels of COT protein were evident in tissue from patients whose tumors returned or relapsed, following drug treatment. “Although we need to extend these results to larger numbers of samples, this is tantalizing clinical evidence that COT plays a role in at least some relapsing melanomas,” added Garraway.One of the critical applications of this work is to identify drugs that can be used to overcome RAF inhibitor resistance. The findings of the Nature paper suggest that a combination of therapies directed against the MAP kinase pathway — the pathway in which both B-RAF and COT are known to act — could prove effective.“We have no doubt that other resistance mechanisms are also going to be important in B-RAF mutant melanoma,” said Garraway, “but by taking a systematic approach, we should be able to find them.” The past year has brought to light both the promise and the frustration of developing new drugs to treat melanoma, the most deadly form of skin cancer. Early clinical tests of a candidate drug aimed at a crucial cancer-causing gene revealed impressive results in patients whose cancers resisted all currently available treatments. Unfortunately, those effects proved short-lived, as the tumors invariably returned a few months later, able to withstand the same drug to which they first succumbed. Adding to the disappointment, the reasons behind these relapses were unclear.
Crews had been working since Saturday’s blizzard to have the railroad fully operational by the beginning of the week.Rail yards were buried in two feet of snow and tracks were blanketed in mounds of white stuff due to the powerful Nor’easter that rolled in on Saturday. On Sunday, officials said they were hoping to have full service restored by Monday morning. But five branches remained closed Monday and only one other line was restored in time for riders to head back to the Island for the evening commute.Nowakowski said thousands of railroad employees had been working to clear snow and repair damaged equipment.“I thank them all for a job well done fighting a snowstorm that hit us harder than expected,” Nowakowski said.The delays Nowakowski had warned riders about materialized early Tuesday morning. There were scattered delays of up to 10 minutes due to ongoing effects from the storm, the LIRR said.About an hour later, however, service was running on or close to schedule. Sign up for our COVID-19 newsletter to stay up-to-date on the latest coronavirus news throughout New York Relief finally came to Long Island Rail Road riders Tuesday as the railroad returned to full service following a headache-filled commute a day earlier.All LIRR branches were fully restored in time for Tuesday morning’s commute, railroad officials said. The restoration of service comes one day after riders were forced to deal with cancellations, delays, and packed trains following this weekend’s blizzard.“We expect to have all segments of all branches operating Tuesday morning, but customers should allow extra travel time and check for the potential for weather-related delays before traveling,” LIRR President Patrick Nowakowski said in a statement.
Promoted Content7 Of The Wealthiest Universities In The WorldDisney’s Live-Action Simba Was Based On The Cutest Lion Cub Ever12 Countries With Higest Technology In The WorldCouples Who Celebrated Their Union In A Unique, Unforgettable WayYou’ve Only Seen Such Colorful Hairdos In A Handful Of AnimeWho Is The Most Powerful Woman On Earth?10 Stargazing Locations To ‘Connect With Nature’5 Of The World’s Most Unique Theme ParksMysterious Astrological Discoveries That Left Scientists Baffled8 Best 1980s High Tech GadgetsWhich Country Is The Most Romantic In The World?8 Superfoods For Growing Hair Back And Stimulating Its Growth The mysterious and potentially all-embracing “other” spending category is said to have accounted for $10.9 million (£8.6 million/€9.6 million) – again, a hefty sum. It seems possible that some of the federation’s legal costs might be bracketed in this item, but this can be no more than speculation at this point. The report also suggests that the body’s revenues may have climbed to some $55 million (£43.4 million/€48.7 million) last year, which was, to repeat, a World Championship year. To speculate further, these leaked figures suggest that World Athletics’ revenues over a full Olympic cycle may amount to something in the order of $200 million (£157 million/€177 million). It received $40 million (£31.5 million/€35.4 million) as its share of the broadcasting revenues generated by the Rio 2016 Olympics, down from $45.2 million (£35.6 million/€40 million) for London 2012. This in turn suggests that the subsidy World Athletics receives from the International Olympic Committee in exchange for the sport’s contribution to the Olympic programme amounts to somewhere in the vicinity of 20 per cent of quadrennial revenues. read also:World Athletics set 2030 target to become carbon neutral The leaked figures put the athletics body’s end-2018 reserves at $45.2 million – high enough to indicate that it probably retains a reasonable cushion to help see it through the present coronavirus crisis, notwithstanding the Tokyo 2020 postponement. World Athletics provided a lengthy statement to The Sports Examiner, but told insidethegames it could not comment on the figures themselves. FacebookTwitterWhatsAppEmail分享 In 2018, the organisation’s revenues are put at $47.5 million (£37.4 million/€42 million), compared with expenses of $66.8 million (£52.7 million/€59.1 million), to leave an apparent deficit of $19.3 million (£15.2 million/€17 million). In 2017, revenues were said to have amounted to $40.5 million (£31.9 million/€35.8 million) and expenses of $60.1 million (£47.4 million/€53.2 million), an apparent deficit of $19.6 million (£15.4 million/€17.3 million). The figures were obtained by The Sports Examiner, which reports having received a phone call from an unidentified individual claiming to have knowledge of financial information provided to delegates at the Congress in Doha that preceded last year’s World Athletics Championships. Following the recent publication of accounts by the International Modern Pentathlon Union, World Athletics is believed to have been the only remaining Summer Olympic International Sports Federation (IF) for which essentially no financial information was in the public domain. An official of what was then the International Association of Athletics Federations (IAAF) told insidethegames in 2015 that: “The IAAF since its move from London in 1984 is established under the laws of Monaco – see Article One of our constitution – and is not obliged and has never published its audited accounts beyond its national members.” The new report gives a breakdown of 2018 expenses. Administration was said to have accounted for $17.3 million (£13.6 million/€15.3 million) of the $66.8 million (£52.7 million/€59.1 million) total, with events absorbing $16.7 million (£13.1 million/€14.7 million), federation support $10.4 million (£8.2 million/€9 million), development just over $3 million (£2.3 million/€2.6 million) and communications $1.3 million (£1 million/€1.1 million). Costs associated with the Athletics Integrity Unit were put at a substantial $7.1 million (£5.6 million/€6.2 million). Loading… Figures detailing the financial performance of World Athletics have at long last emerged, showing that the body made hefty deficits in both 2017 and 2018.