When skin cancer cells resist drug treatment

first_imgOne of cancer’s most frightening characteristics is its ability to return after treatment. In the case of many forms of cancer, including the skin cancer known as melanoma, tailored drugs can eradicate cancer cells in the lab, but often produce only partial, temporary responses in patients. Thus the burning question in the field of cancer research remains: How does cancer evade drug treatment?New research by a team from the Broad Institute of Harvard and MIT, and Harvard affiliates Dana-Farber Cancer Institute (DFCI) and Massachusetts General Hospital (MGH) suggests that some of the answers to this question do not lie in cancer cells themselves. To find the answers, scientists are looking beyond tumor cells, studying the interplay between cancer cells and their healthy counterparts. The research team has found that normal cells that reside within the tumor, part of the tumor microenvironment, may supply factors that help cancer cells grow and survive despite the presence of anti-cancer drugs. These findings appear online this week in a paper published in Nature.“Historically, researchers would go to great lengths to pluck out tumor cells from a sample and discard the rest of the tissue,” said senior author Todd Golub, director of the Broad’s Cancer Program and Charles A. Dana Investigator in Human Cancer Genetics at the DFCI. Golub is also a professor at Harvard Medical School (HMS) and an investigator at Howard Hughes Medical Institute. “But what we’re finding now is that those nontumor cells that make up the microenvironment may be an important source of drug resistance.”To investigate how the tumor microenvironment may contribute to drug resistance, the researchers designed experiments in which cancer cells were grown in the same wells (miniscule test tubes no larger than a pencil eraser) along with normal cells. These co-cultured cells were then treated with anti-cancer drugs. When grown alone, such cancer cells died in the presence of many of these targeted agents, but when grown together with normal cells, cancer cells developed resistance to more than half of the 23 agents tested.These observations reflect what clinicians often see in patients with cancers such as melanoma. In the case of melanoma, targeted therapies have been developed against a specific, common mutation in a gene known as BRAF. While some patients’ tumors show an overwhelming response to BRAF inhibitors and seem to disappear, other patients’ tumors only respond by slightly decreasing in size. The failure to shrink tumors at the outset suggests that those tumors possess some level of innate resistance — the ability to evade drugs from the beginning of treatment.“Even though recent advances in targeted therapy have caused tremendous excitement in melanoma, the fact remains that drug resistance eventually develops in nearly all metastatic melanomas treated with BRAF inhibitors, and in some cases is present at the outset of treatment,” said Levi A. Garraway, a senior associate member of the Broad Institute and an associate professor at DFCI and HMS.“There are many different types of mechanisms that tumors may hijack to circumvent the effects of therapy … no single experimental approach can capture all of these potential mechanisms,” Garraway continued. “Thus, the application of complementary approaches can offer considerable synergy in terms of discovering the full spectrum of clinically relevant resistance mechanisms.”Scientists have uncovered resistance mechanisms that cancer cells develop over time — genetic changes in specific genes that may give cancer the ability to overcome the effects of a drug with time — but these acquired resistance mechanisms do not explain the innate resistance seen in many tumors.“We can take cancer cells out of a melanoma patient, put them on a dish, and most times they will turn out to be extremely sensitive to the targeted agents, but that’s not what we see in patients,” said Ravid Straussman, a postdoctoral fellow at the Broad Institute and first author of the Nature paper. “Why do we get just a partial response in most patients? We set out to dissect this question, and the next logical step was to think beyond cancer cells.”After completing systematic, high-throughput screens of more than 40 cancer cell lines, the researchers chose to focus on melanoma, looking at whether factors normal cells secrete help cancer cells resist treatment. They measured more than 500 secreted factors and found that the factor most closely linked to BRAF inhibitor drug resistance was hepatocyte growth factor (HGF). HGF interacts with the MET receptor, abnormal activation of which has been tied to tumor growth in previous studies but never to drug resistance in melanoma.In addition to studying cells in the lab, the research team sought to replicate their findings in samples from cancer patients. Keith Flaherty, director of developmental therapeutics at MGH Cancer Center and an associate professor at HMS, and his lab provided 34 patient samples for study. The team measured levels of HGF in these samples and saw a relationship between how much HGF was present and the amount of tumor shrinkage patients experienced. For example, tumors in patients with high levels of HGF shrank less than those in patients with low HGF levels.“To try to explore in patient samples what factors in the microenvironment are not only present but functionally important in drug resistance would have been largely impossible. Coming up with candidates in the lab and then exploring relevance in humans in a targeted way is the only tractable approach,” said Flaherty. “By taking this high-throughput screening, hypothesis-generating approach, we could then follow up by looking at patient samples. In a case like melanoma, where you already have a targeted therapy available, it puts you on good footing to narrow in on specific factors that may be at play in drug resistance.”Several HGF/MET inhibitors are in clinical development or are FDA-approved for other indications, making clinical trials combining these inhibitors with BRAF inhibitors feasible in the future. In addition, researchers could follow the same approach taken by the team to screen other drugs currently in development, identifying mechanisms of resistance and ways to counter them even before treatment begins.“Drug resistance should no longer surprise us,” said Golub. “We’re thinking about how to do this — how to systematically dissect resistance — much earlier in the drug development process so that by the time a new drug enters the clinic, we have a good sense of what the likely mechanisms of resistance will be and have a strategy to combat them.”This work was supported by the Howard Hughes Medical Institute, National Cancer Institute grants, and a Melanoma Research Alliance Team Science Award.last_img read more


first_imgDunfanaghy Golf Club NotesIt was Lady Captain’s week and what a great week we have had on the course and in the clubhouse.There was the Lady and Gent’s Captain’s prizes to the Juveniles on Thursday. There were 40 juveniles taking part in the competitions and there was some great scoring. Well done to one and all who took part. And thanks to all the parents that assisted on the evening. Then we had the scramble on Friday and there was a great turnout of both young and old on a beautiful evening. Mal Johnson was ready with the barbeque when the golfers were finished. And the burgers were so good most people had two. Well done Mal.Then on Saturday it was Cheryl’s Lady Captain’s prize day here at the club and on behalf of the Gent’s committee I would like to congratulate Cheryl on a most enjoyable sequence of competitions over the past week. Lady Captain’s Day was a tremendous success and a fitting reward for her tremendous work on behalf of the club throughout the year. Congratulations also to Deborah Moore on winning this prestigious event at the very first attempt. There was a huge turnout on the day and the weather was fantastic. We were very lucky as it had rained heavily in neighbouring towns. The attention to detail by Cheryl was second to none and the clubhouse looked fabulous. The food was fantastic and the music during the day and night kept everyone entertained.Results:Lady Captain Results Saturday 9th August 2014 1st Deborah Moore 41pts2nd Karen McCormick 40ptsGross Maggie Foy 26pts3rd Margaret Roarty 39pts4th Rosie Agnew 38pts 5th Lyn McOwan 37pts9s Sandra McGinley 20pts & Siobhan Bogues 21ptsStudent Amy & RachelLady Guest Rosanne Logue 37pts 14 Hole Gretta Sweeney 23ptsPast Captain Margaret Witherow 37ptsCommittee Olivia Moore 37ptsNon Qual. Margaret McKee 38ptsLongest Drive Natalie CummingsNearest the pin Rosie AgnewCSS 36ptsLady Captain’s Prize to Gents Sat 9th August,1st Colin Higgs 40pts2nd Brendan Kelly 39ptsGross Keith Lapsley 34 pts3rd Willie Wilkin 39pts9’s Paul Smyth 20pts & Chris Marriott 22ptsCSS 37 ptsMonday sees the start of Captain’s week and once again on behalf of all our members I would like to wish Captain Gerald every success. During his tenure as Captain we have witnessed growth in all aspects of life here at the club. The course is in the best shape it has ever been, membership is up quite substantially, and in the clubhouse the bar and kitchen are proving extremely popular with members and visitors alike. All of this increased activity has had a very positive effect on our finances, so if this momentum can be maintained we are on track for a very successful year. The feel good factor which currently exists within the club can be attributed in no small measure to the leadership shown by our Captain. His drive, energy and attention to detail are absolutely incredible while his “can do” attitude seems to bring out the best in those around him. It has been an absolute pleasure to have worked alongside such an enthusiastic, dedicated and forward thinking Captain so let us all give him the support he so richly deserves up to and including his big day on Saturday. Lets hope the weather is as kind to Gerald during the week and especially next Saturday. The full list of competitions for the week is listed below. Let’s try and play as many of the competitions during the week and visit the clubhouse as there should be a great atmosphere in the clubhouse all week.As it is Men’s Captain’s weekend, the scramble will be 18 holes. You have to register before 4pm on Friday with the Shotgun Start at 4.30pm.The competitions are as follows:Competitions this coming week:• Tuesday 12th August Men’s Captain’s prize to the Ladies• Wednesday 13th August Open Singles Stableford• Thursday 14th August Captain’s mixed Foursomes• Friday 15th August 18 hole scramble register by 4pm for 4.30pm start• Saturday 16th August Men’s Captain Prize• Sunday 17th August 4BBB any combinationAs everyone that has been in the clubhouse over the weekend would have seen, we have posters up which mention the Ryder cup Weekend. This will be launched on the Caravanner’s weekend. You have been warned to make sure to have the 26th-28th of September free as it promises to be a great weekend. All details will be announced on the Caravanner’s weekend. The timesheet is up for the Caravanner’s classic, so get your name down on the timesheet as soon as possible.Juvenile notes;What a busy week it has been for the juvenile members. It started with the main event of the year the Captains Prize and a large turnout taking to the fairways. The best golf was played by Kyle Mc Garvey who followed up last years major win in the Presidents Prize to lift the Captains Prize with a little bit to spare. Two majors in two years, Kyle is now chasing Rory. In second place was James Sweeney with Conor Gallagher filling third place. In the Cadet section Ben Smyth led the way with Hugh Burke in second and Ciaran Moore fresh from his recent success in the Foyle Cup taking third.Sarah Sweeney came out on top in the Girls section with Danielle Mullan second and Rachael Dolan third. It was great to see many girls out on the course.The normal Saturday morning competition was a very close affair with a 2 hole play off need to decide the winner with James Sweeney just getting the better of Conor Hanna. In the Cadets Eoin Bonner played great golf to take first from Ben Smyth.There will be no competition next Saturday morning due the Captains Prize taking place, we will contact members re the next competition date.GOLF NEWS: DEBORAH MOORE WINS THE LADY CAPTAINS PRIZE AT DUNFANAGHY was last modified: August 12th, 2014 by Mark ForkerShare this:Click to share on Facebook (Opens in new window)Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Reddit (Opens in new window)Click to share on Pocket (Opens in new window)Click to share on Telegram (Opens in new window)Click to share on WhatsApp (Opens in new window)Click to share on Skype (Opens in new window)Click to print (Opens in new window)Tags:DunfanaghygolfNoticesSportlast_img read more

Thieves strike at judge’s house, steal trees in Madhya Pradesh

first_imgA gang of five thieves struck at the residence of Arun Kumar Singh, a district court judge and chopped off four sandalwood trees from the premises, before decamping with the logs, police said on Saturday. Police said Justice Singh and his family members were asleep when the incident took place, adding that the thieves cut the trees after threatening the judge’s police guard at gunpoint.The incident took place during the intervening night of Thursday and Friday, police said, adding that the thieves cut the trees after threatening the judge’s police guard at gunpoint.The police guard, Budhi Lal Kol, lodged a complaint with the police in this regard.“As per the complaint, one of the thieves first entered district and sessions court judge Arun Kumar Singh’s bungalow in Civil Lines area on the intervening night of November 14 and 15. He threatened Kol with a country-made pistol. Soon, four other accomplices joined him and held the guard captive,” City Superintendent of Police Shivendra Singh told PTI.“Within 10 minutes, the accused cut the sandalwood trees and fled with the logs. Total four guards, including Kol, were stationed at different locations at the bungalow when the incident took place. However, the thieves did not harm anyone,” he said.Police said the judge and his family members were asleep when the incident took place. According to Singh, police suspect that the accused were from Uttar Pradesh’s Kannauj, which is home to several manufacturing units of incense sticks and perfumes.“In the past, Rewa police had arrested some people from Kannauj for cutting and stealing sandalwood trees from the city,” the CSP said.“Sandalwood is used in making incense sticks and perfume. The cost of the trees stolen from the judge’s house could be around ₹3 to 5 lakh,” he said. Singh said that police have registered a case in this connection and launched a search to catch the accused.last_img read more

CWC 2018 Real Madrid and Al Ain are set to make

first_imgBoth teams are playing for important objectives: Real Madrid wants its third consecutive world title, while Al Ain wants to be the first non-European/South American championTomorrow, football fans have a date with history as the Grand Final of the 2018 FIFA Club World Cup is set to play.Spanish La Liga giants Real Madrid will take on local Emirati surprise club Al Ain FC, to decide who is the best team in the planet.And both sides are playing for important objectives.Madrid is participating in its fourth FIFA Club World Cup Final, and third consecutive, and want to become the biggest champion in the tournament.They are currently tied with three tiles with fellow Spanish team Barcelona.Meanwhile, Al Ain FC has surprised the world, not only by beating New Zealand’s Team Wellington in the Playoff match, but also defeating Espérance Sportif de Tunis in the Quarterfinals.Sergio Ramos, Real MadridZidane reveals Sergio Ramos injury concern for Real Madrid Andrew Smyth – September 14, 2019 Zinedine Zidane has put Sergio Ramos’ availability for Real Madrid’s trip to Sevilla next weekend in doubt after withdrawing him against Levante.The Boss then defeated Copa Libertadores king River Plate, in a surprising match that had to be decided in penalty kicks.This means, that they have the chance to become the first non-European/South American champion in the tournament’s history.Before this match, Argentina’s River Plate will take on Japanese and Asian champions Kashima Antlers to settle the Third Place of the CWC.Who do you think will win the tournament this Saturday?#CWC18: You can follow all our coverage of the FIFA Club World Cup in our different social media. @ClubWorldCups pic.twitter.com/0BmSDpo0kQ— Ronaldo.com (@ronaldocomint) December 15, 2018last_img read more