They began with a discovery in zebrafish in 2007, and now researchers at the Harvard Stem Cell Institute (HSCI) have published initial results of a Phase Ib human clinical trial of a therapeutic that could improve the success of blood stem cell transplantation. This marks the first time that HSCI has carried a discovery from the lab bench to the clinic, fulfilling the promise of Harvard’s major commitment to such research by founding the institute nine years ago.The Phase Ib safety study, published in the journal Blood, included 12 adult patients undergoing umbilical cord blood transplantation for leukemia or lymphoma at the Dana-Farber Cancer Institute and Massachusetts General Hospital (MGH). Each patient received two umbilical cord blood units, one untreated and the other treated with the small molecule 16,16-dimethyl prostaglandin E2 (dmPGE2). All 12 patients had reconstitution of their immune systems and renewed blood formation, and 10 of the 12 had blood formation derived solely from the kdmPGE2-treated umbilical cord blood unit.The clinical testing is now entering Phase II, which will assess the treatment’s efficacy at eight medical centers with 60 patients. Results are expected in 18–24 months.Like much of the work conducted under the HSCI umbrella, this “first” depended on the collaboration of scientists at different Harvard-affiliated institutions, and in this case an industrial partner:The initial finding occurred in the laboratory of Leonard Zon, chair of the HSCI Executive Committee and professor of stem cell and regenerative biology at Harvard, who studies blood formation in zebrafish at Children’s Hospital Boston;Clinical research was conducted at Dana-Farber and MGH, led by hematologic oncologist and HSCI-affiliated faculty member Corey Cutler; andFate Therapeutics, a San Diego-based biopharmaceutical company of which Zon is a founder, sponsored the investigational new drug application, under which the clinical program was conducted, and translated the research findings from the laboratory into the clinical setting.“The exciting part of this was the laboratory, industry, and clinical collaboration, because one would not expect that much close interplay in a very exploratory trial,” Cutler said. “The fact that we were able to translate someone’s scientific discovery from down the hall into a patient just a few hundred yards away is the beauty of working here.”Gastroenterologists have studied dmPGE2 for decades because of its ability to protect the intestinal lining from stress. However, its ability to amplify stem cell populations — the first molecule discovered in any system to have such an effect — was identified in 2005 during a chemical screen exposing 5,000 known drugs to zebrafish embryos. That work, published in the journal Nature in 2007, was conducted by Wolfram Goessling and Trista North, both former Zon postdoctoral fellows and current HSCI principal faculty members.“We were interested in finding a chemical that could amplify blood stem cells, and we realized in looking at zebrafish embryos that you could actually see blood stem cells budding from the animal’s aorta,” Zon said. “So we elected to add chemicals to the water of fish embryos, and when we took them out and stained the aortas for blood stem cells, there was one of the chemicals, which is 16,16-dimethyl prostaglandin E2, that gave an incredible expansion of stem cells — about a 300 to 400 percent increase.”The dramatic effects of this molecule on blood stem cells made Zon, a pediatric hematologist, consider ways in which prostaglandin could be applied to bone marrow transplantation, often used to treat blood cancers, including leukemia and lymphoma. Bone marrow contains the body’s most plentiful reservoir of blood stem cells, so patients with these conditions may be given bone marrow transplants to reconstitute their immune systems after their cancer-ravaged systems are wiped out by chemotherapy and radiation.Zon designed a preclinical experiment, similar to one later done with cord blood patients, in which mice undergoing bone marrow transplants received two sets of competing bone marrow stem cells, one set treated with dmPGE2 and the other untreated.“What we found was the bone marrow stem cells that were treated with prostaglandin, even for just two hours, had a four times better chance of engrafting in the recipient’s marrow after transplant,” he said. “I was very excited to move this into the clinic because I knew it was an interesting molecule.”The next step for Zon and his team was to visit Dana-Farber, where they presented the mouse research at bone marrow transplant rounds and found physicians interested in giving the prostaglandin to patients.“We basically sat down in a room, and we brainstormed a clinical trial based on their scientific discovery, right then and there,” said Cutler. “They knew that it was something they could bring to the clinic, but they just didn’t know where it would fit. We said, if this molecule does what you say it does, significant utility would lie in umbilical cord blood transplants.”A cord blood transplant is similar to a bone marrow transplant. However, the blood stem cells are derived from the umbilical cord blood of a newborn rather than from an adult donor. One of the advantages of umbilical cord blood is that matching between donor and recipient does not need to be as exact, because potentially fatal graft-versus-host disease is less common. Although about 10-20 percent of stem cell transplantation procedures now use umbilical cord blood, the downside is that engraftment is more difficult because the number of stem cells in an umbilical cord blood donation is far fewer than in an adult stem cell donation.Umbilical cord blood transplants fail about 10 percent of the time. So increasing the procedure’s success would significantly help patients who do not have adult bone marrow donors, including a disproportionate number of non-Caucasian patients in North America. Increasing the engraftment rate would also allow the use of smaller umbilical cord blood units that could be better matches to their recipients, increasing the number of donations that go on to help patients.Once Fate Therapeutics received the go-ahead for the trial from the U.S. Food and Drug Administration and Dana-Farber’s Institutional Review Board, the umbilical cord blood processing was done by the hospital’s Cell Manipulation Core Facility, directed by HSCI Executive Committee member Jerome Ritz. The study hit a stumbling block, however, once the human trial with the first nine patients got under way. The protocol that produced the dramatic blood stem cell expansion in mice did not translate to improved engraftment in humans.“The initial results were very disappointing,” Cutler said. “We went back to the drawing board and tried to figure out why, and it turned out some of the laboratory-based conditions were simply not optimized, and that was largely because when you do something in the lab, the conditions are a little bit different than when you do it in a human.”Fate Therapeutics discovered that the human cord blood was being handled at temperatures of 4 degrees Celsius — too cold for the prostaglandin to biologically activate the stem cells and improve their engraftment properties. The company further demonstrated that performing the incubation of the hematopoietic stem cells at 37 degrees Celsius and increasing the incubation time from one to two hours elicited a much stronger gene and protein expression response that correlated with improved engraftment in animal models.In running a second cohort of the Phase Ib trial, which included 12 patients, dmPGE2 appeared to enhance the engraftment properties of the blood stem cells in humans and was deemed safe to continue into Phase II.“It’s probably the most exciting thing I’ve ever done,” Zon said. “Basically, to watch something come from your laboratory and then go all the way to a clinical trial is quite remarkable and very satisfying.”The research was funded by the National Institutes of Health, the Howard Hughes Medical Institute, the Stem Cell Cyclists of the Pan-Mass Challenge, and the Patrick Carney Foundation.
8SHARESShareShareSharePrintMailGooglePinterestDiggRedditStumbleuponDeliciousBufferTumblr Think of the first three letters Differentiate, Recreate and Educate as the ingredients to bake a one-of-a-kind-out-of-this-world-cake. Now we put them all together and automate (or bake) it.Kirk recommends the new member experience be the first place to try marketing automation.I recently sat in on a conference call regarding Net Promoter Score and found out that most credit unions are not “blowing members away” when they open up their new account. In fact, very few members will give a promoter score citing “Too early to tell” or “I just opened the account and I don’t feel I know them yet.”But this was even more disconcerting. In a Pacific NW study of credit unions and banks they found that Chase AND Bank of America scored higher with Millennials (18-34) on the “overall recommend” question. They did not cite service as the reason but rather just the opposite. They do a great job making it possible for the Millennial customer to NEVER have to interact with a human. And they do that using automation. continue reading »
WEST Indies ‘A’ all-rounder Rahkeem Cornwall is harbouring hopes of breaking into the regional side in the near future after being selected for an ‘A’ team to face India ‘A’ next month.The big-hitting all-rounder from Antigua, along with former West Indies batsman Devon Thomas, was selected as part of a Windies ‘A’ side that will take on India ‘A’ in five One-Day games. The two have also been selected for the first two four-day encounters between the sides.“It feels good to be back as part of the ‘A’ squad after being left out during the England series for what reason I don’t really know, but it’s good to be back. I just have to go and put in a good performance and see what comes up for the senior team selection,” said Cornwall.“My goal is just to go and perform to see if I can get into the ODI team and then whenever the opportunity comes around for the two warm-up four-day games, I just keep doing the same thing and see what happens at the end of the day,” he added.Cornwall, after being dropped, resumed his fitness programme with the West Indies’ High Performance Centre, and believes the initiative has borne fruit.“I think it has equipped me even better than before because I feel the big change. I feel different in terms of even local cricket where the movements and so on are way better than before.“I am just going to keep my fitness level and everything else in order and probably a week or so before I start, to tone down a bit to get the muscles ready cricket-wise, play one or two local games to get that cricket fitness under my belt,” he said.India ‘A’ will face the Windies ‘A’ in the first one-day game on July 11 before playing again on the 14th and 16th at the Sir Vivian Richards Cricket Ground, while the final two games at the Coolidge Cricket Ground will take place on July 19 and 21.The first unofficial Test takes place on July 31 at Sir Vivian Richards Stadium with the second on August 6 at Brian Lara Cricket Academy.
Syracuse men’s club hockey coaches Nick Pierandri and Andrew Wolinski got their starts playing hockey at the Salisbury and Kent Schools respectively, two of the top prep school programs in both New England and the country.For Wolinski, who doubles as the team’s recruiting coordinator, his history with the area was only one of the reasons why SU’s first-ever recruitment search started there.Freshmen forwards Zach Bunick, Ben King and Rob VanRaamsdonk may represent the future for Syracuse men’s club hockey (8-7). As the first recruiting class in team history, the three former prep school athletes out of New England’s elite Division I hockey association are a key part of Pierandri’s push as a second-year head coach to reach the top of collegiate club hockey.“That’s a little bit of our bias,” Wolinski said. “There’s a very hard academic rigor at prep school so we know the quality of student we’re getting is better. They’re used to a lot of structure and a lot of demand from teachers.”Wolinski handles the inquiries of interested recruits, raises awareness for the pro-gram and attends a number of tournaments in search of potential athletes — using money out of his own salary from coaching. It was at one of these tournaments, the Chowder Cup in Boston, that Wolinski found King, who then attended the Millbrook School in Millbrook, New York.AdvertisementThis is placeholder textSU “wasn’t even on the map,” King said, before he met Wolinski, but that began to change after talking to and exchanging numbers with the assistant coach.Unlike the NCAA programs King was in contact with, Syracuse’s club team didn’t re-quest for King to take a year off to play juniors hockey to develop more. For King, who had already lost a year by transferring to prep school, this made SU all the more attractive.The school that wasn’t on the map eventually became King’s school of choice, which he decided after an overnight visit at SU. Similar to many NCAA programs, the Or-ange coaches planned the overnights, which consisted of watching practices, talking to coaches and staying with a member of the team.It was at the overnight that King met VanRaamsdonk, who he would eventually be-come roommates with after both decided to attend SU.“We didn’t want to go random and we just thought that we were both on the team so it would just be easy and work out,” VanRaamsdonk said.The three recruits, particularly Bunick, have had an immediate effect in the first half of the season. The speedy Rivers School graduate quickly became a leader for the Orange offense, ranking second in total points scored, despite not appearing in two of the team’s 15 games.For Bunick, an S.I. Newhouse School of Public Communications student that was ac-cepted after applying early decision, hockey was what “sealed the deal” in making SU his choice. Now, he and his fellow recruits hope to do whatever they can to help bring victories to the Orange.“We’ve just been trying to do our role,” Bunick said. “The first couple weeks we were given a role of what to do, whether it was to score goals, be a playmaker (or) block shots. We all came into those roles and just tried to help the team win.” Comments Facebook Twitter Google+ Published on November 12, 2014 at 12:05 am