Improving cord blood transplants

first_imgThey 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.last_img read more

"Improving cord blood transplants"

Spurs hope for 2017 stadium switch

first_img That depends, though, on the outcome of the public inquiry which was held last April and which has delayed the acquisition of the remaining property needed for the land to build the stadium. The club are waiting for a decision from Eric Pickles, the s ecretary of state for communities and local government, on the compulsory purchase order. Tottenham chairman Daniel Levy said: “We have fantastic, strong support. Our current 36,000-seater stadium sells out and the waiting list for season ticket holders is currently in excess of 47,000. “We cannot stress strongly enough how critical the new stadium is over the long term to these raised expectations. “We have the smallest capacity stadium of any club in the top 20 clubs in Europe, let alone the current top four Premier League clubs, and given we now operate within UEFA Financial Fair Play rules, an increased capacity stadium and associated revenues is fundamental to supporting the future ambitions and consistent achievement at the top of the game. “Our focus therefore is to continue to invest in and develop the squad – we shall not look to a summer of major upheaval, but rather to strengthen in key positions – to play the style of football for which we are famous – and to deliver the new stadium.” Spurs announced a profit for the year ending June 30, 2013 after tax and interest of £1.5million, having made a £4.3million loss in 2012. Tottenham have announced they could leave White Hart Lane for a new stadium in three years. In announcing their financial results, the club said their new stadium could open as early as the summer of 2017. A statement from Tottenham read: “It is a major development that will present ongoing challenges and, subject to these challenges being manageable, we anticipate going out to tender for construction late this year which will make a stadium opening date of summer 2017 feasible.” center_img Press Associationlast_img read more

"Spurs hope for 2017 stadium switch"

Cricket News Where will Shikhar Dhawan go in IPL 2019 – Delhi Daredevils or Kings XI Punjab?

first_img For all the Latest Sports News News, Cricket News News, Download News Nation Android and iOS Mobile Apps. New Delhi: Shikhar Dhawan, who has been a key player for Sunrisers Hyderabad in the Indian Premier League, could head back to the Delhi Daredevils for the 2019 edition, according to sources. Earlier, there were reports that Dhawan could head to Kings XI Punjab.According to an ESPNCricinfo report, Dhawan, who played for Delhi Daredevils in the 2008 season, is not happy about his price tag and this has resulted in Sunrisers Hyderabad releasing him through the trading window. In the 2018 auctions, the Sunrisers Hyderabad franchise paid Rs 5.2 crore to retain the left-hander. Read More | Cricket Australia’s ‘arrogant’, ‘controlling’ culture criticisedAfter playing IPL 2008 for the Daredevils, Dhawan moved to Mumbai Indians and played for the franchise in 2009 and 2010. In 2011, Deccan Chargers brought Dhawan for $300,000 but following the disbanding of the franchise in 2012, the Indian cricket team opener became one of the key players for the new franchise Sunrisers Hyderabad.Read More | Pakistan whitewash Australia 3-0 in Twenty20 InternationalsDhawan is the leading run-getter in the IPL for Sunrisers Hyderabad, scoring 4058 runs in 143 games at an average of 33 and a strike-rate of 123. His best performance came in the 2016 season, when he smashed 501 runs at an average of 38 and along with David Warner, helped Sunrisers Hyderabad clinch the IPL title. Trade-offs in IPLBoth Dhawan and Delhi Daredevils have not released a public statement. If this deal goes through, then Dhawan will be the third player to have been traded off to another franchise in this period before the auction. Quinton de Kock was traded to Mumbai Indians from Royal Challengers Bangalore in what was a money-only trade. This trade involves paying money to the franchise and not replacing an existing player in the team. Mandeep Singh, who played for Royal Challengers Bangalore, has been traded to his home town team of Kings XI Punjab in place of Australia all-rounder Marcus Stoinis. The next IPL auction is scheduled on December 16 while some portion of the IPL in 2019 could be played outside of India in the wake of the general elections which will be held early next year. last_img read more

"Cricket News Where will Shikhar Dhawan go in IPL 2019 – Delhi Daredevils or Kings XI Punjab?"

Veikkaus under fire for not fulfilling its responsibility mandates

first_img Submit Share A report commissioned by Finland’s National Institute for Health & Welfare (THL) has warned state-monopoly Veikkaus and media stakeholders that gambling advertising is not in-line with the nation’s public health interests.Speaking to national broadcaster Yle.fi, THL senior researcher Jani Selin stated that Veikkaus advertising messages had failed to convey the public health risks attached to gambling.“The advertising slogans of Veikkaus are at odds with public health communication. Veikkaus’ marketing sends very different messages than those about the dangers of gambling. They should be consistent and in keeping with the way that other harmful products are marketed,” Jani Selin detailed to Yle.Furthermore, Veikkaus position as state gambling monopoly has come under the scrutiny of Finland’s Social Affairs Ministry which detailed last month that the operator had failed to curb problem gambling rates, a key directive in Veikkaus absorbing RAY and Fintoto enterprises back in 2017.In its report, the THL urges the Finnish government to review Veikkaus €50 million advertising account, restricting the promotion of ‘high risk games’ and volume of Veikkaus advertising.Veikkaus Managing Director Velipekka Nummikoski would issue a statement defending the firm’s advertising practices, stating that Veikkaus has always followed a social mandate promoting low-risk ‘green games’.Nummikoski, detailed that problem gambling concerns should be attributed to foreign unlicensed operators, that could still target national consumers through multiple media channels, and that are not restricted public access by Finland’s legal frameworks. Veikkaus calls for early introduction of Finnish age verification measures August 28, 2020 Related Articles StumbleUpon Share Lottery leaders to address COVID-19 crisis at SBC Digital Summit April 17, 2020 Veikkaus seeks new wagering lead as Kauhanen departs to lead Finnish Hippos June 12, 2020last_img read more

"Veikkaus under fire for not fulfilling its responsibility mandates"