Target Health is Co-Presenting at BIO on a Panel on Risk-Based Monitoring
Dr. Jules T. Mitchel will be presenting at a Panel at the BIO International Convention in Chicago (April 22-25). The panel is entitled Clinical Trials Modernization: The Promises and Challenges of Risk-Based Approaches to Monitoring, and will be held on April 24 at 10:30 am in Building: S401A (Session ID: 1983). Other speakers include James Dixon Senior Vice President, Global Quality & Compliance PPD, Inc. and Ann Meeker-O’Connell Acting Division Director, Good Clinical Practice Compliance CDER, US Food and Drug Administration.
Session Description: Monitoring the progress of clinical investigations typically involves frequent visits to each study site. However, general guidelines for Good Clinical Practice (GCP), FDA regulation, and International Conference on Harmonization (ICH) guideline E6 actually provide substantial latitude regarding the extent and nature of clinical trial monitoring. Newer risk-based approaches that leverage centralized data monitoring through electronic data capture systems can lead to significant efficiencies for clinical trial sponsors. A panel representing industry sponsors of clinical research, clinical research organizations, and regulatory authorities will present their current thinking and strategies to streamline study oversight.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com
Scientists Successfully Map Telomerase Enzyme That Has Rejuvenating Effect On Cells
In collaboration with an international research team, University of Copenhagen researchers have for the first time mapped telomerase, an 1) ___ which has a kind of rejuvenating effect on normal cell aging. The findings have just been published in Nature Genetics and are a step forward in the fight against cancer.
Mapping the cellular fountain of youth — telomerase.
This is one of the results of a major research project involving more than 1,000 researchers worldwide over a four year period. The project cost DKK 55 million from the EU and included blood samples from more than 200,000 people. This is the largest collaboration project ever to be conducted within cancer 2) ___.
Stig E. Bojesen, a researcher at the Faculty of Health and Medicial Sciences, University of Copenhagen, and staff specialist at the Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev, headed the efforts to map 3) ___ — an enzyme capable of creating new ends on cellular chromosomes, the so-called telomeres. In other words, a kind of cellular fountain of youth. “We have discovered that differences in the telomeric gene are associated both with the risk of various cancers and with the length of the telomeres. The surprising finding was that the variants that caused the 4) ___ were not the same as the ones which changed the length of the telomeres. This suggests that telomerase plays a far more complex role than previously assumed,” says Stig E. Bojesen.
The mapping of telomerase is an important discovery, because telomerase is one of the very basic enzymes in cell 5) ___. It re-lengthens the telomeres so that they get the same length as before embarking on cell division. “The mapping of telomerase may, among other things, boost our knowledge of cancers and their treatment, and with the new findings the genetic correlation between 6) ___ and telomere length has been thoroughly illustrated for the first time,” says Stig E. Bojesen.
The human body consists of 50,000,000,000,000 or fifty trillion cells, and each cell has 46 chromosomes which are the structures in the nucleus containing our hereditary material, the 7) ___. The ends of all chromosomes are protected by so-called telomeres. The telomeres serve to protect the chromosomes in much the same way as the plastic sheath on the end of a shoelace. But each time a cell divides, the telomeres become a little bit shorter and eventually end up being too short to protect the 8) ___. Popularly speaking, each cell has a multi-ride ticket, and each time the cell divides, the telomeres (the chromosome ends) will use up one ride. Once there are no more rides left, the cell will not divide any more, and will, so to speak, retire. But some special cells in the body can activate telomerase, which again can elongate the telomeres.
Gender cells, or other stem 9) ___ which must be able to divide more than normal cells, have this feature. Unfortunately, cancer cells have discovered the trick, and it is known that they also produce telomerase and thus keep themselves artificially young. The telomerase gene therefore plays an important role in cancer biology, and it is precisely by identifying cancer genes that the researchers imagine that you can improve the identification rate and the treatment.
“A gene is like a country. As you map it, you can see what is going on in the various cities. One of the cities in what could be called Telomerase Land determines whether you develop breast cancer or ovarian cancer, while other parts of the gene determine the length of the telomeres. Mapping telomerase is therefore an important step towards being able to predict the 10) ___ of developing different cancers. In summary, our findings are very surprising and point in many directions. But as is the case with all good research, our work provides many answers but leaves even more questions,” says Stig E. Bojesen.
Researchers in Spain were able to induce cells to express telomerase, which is able to slow down the metabolic clock. This team boosted the lifespan of a mouse by 24% with a single treatment. These scientists published their findings, last year, in the journal EMBO Molecular Medicine. The gene therapy acts on specific genes and is applied in adult life, not from the embryonic stage. Researchers at the Spanish National Cancer Research Center (CNIO) have demonstrated that the mouse lifespan can be extended by the application of one treatment acting directly on the animal’s genes in adult life. The therapy has been found to be safe and effective in 11) ___.
For the study, adult and aged mice were treated with the gene therapy, delivering a rejuvenating effect. On average, the mice lived 24% longer. The older mice lived 13% longer. The therapy produces an appreciable improvement on the animal’s health and delayed the onset of age-related diseases. The genes were treated with a DNA-modified virus. The viral genes were replaced by those of the telomerase enzyme, which plays a key role in aging. Telomerase repairs the extreme ends of chromosomes, and slows the cells and therefore the body’s biological 12) ___.
There is a potential to develop a telomerase-based anti-aging gene therapy that won’t increase the risk of cancer. Telomeres are the caps that protect the end of chromosomes, but each time the cell divides, the telomeres get 13) ___ until they lose all functionality. The cell then stops dividing or dies. Telomerase prevents telomeres from shortening or even rebuilding them. In most cells, telomerase is only active before birth. The cells of adult organisms contain no telomerase. There are some exceptions such as adult stem cells and cancer cells, which divide limitlessly and could be immortal. The risk of cancer tumor promotion is a risk that has set back telomerase-based anti-aging therapies. The kind of virus employed to carry the telomerase gene to the cells is very important. The viruses used in this study have been successfully used in gene therapy treatment of hemophilia and eye disease. They are non-replicating viruses derived from others that are non-pathogenic in 14) ___.
ANSWERS: 1) enzyme; 2) genetics; 3) telomerase; 4) diseases; 5) biology; 6) cancer; 7) DNA; 8) chromosomes; 9) cells; 10) risk; 11) mice; 12) clock; 13) shorter; 14) humans
Elizabeth Blackburn (1948 to present) and Discovering Telomeres
Dr. Elizabeth H. Blackburn
In the early 1970s, Russian theorist Alexei Olovnikov first recognized that chromosomes could not completely replicate their ends. Building on this, and to accommodate Leonard Hayflick’s idea of limited somatic cell division, Olovnikov suggested that DNA sequences are lost every time a cell/DNA replicates until the loss reaches a critical level, at which point cell division ends. Elizabeth Blackburn, working as a postdoctoral fellow at Yale University with Joseph Gall, discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends. Their work was published in 1978. The telomere-shortening mechanism normally limits cells to a fixed number of divisions, and animal studies suggest that this is responsible for aging on the cellular level and sets a limit on life spans. Telomeres protect a cell’s chromosomes from fusing with each other or rearranging – abnormalities that can lead to cancer – and so cells are destroyed when their telomeres are consumed. Most cancers are the result of “immortal” cells that have ways of evading this programmed destruction.
Elizabeth Blackburn, Carol Greider, and Jack Szostak were awarded the 2009 Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.
Carol W. Greider, now at Johns Hopkins, found the enzyme telomerase, which restores telomeres
Scientists are trained to be skeptics, and Elizabeth H. Blackburn considers herself one of the biggest. Show her the data, and be ready to defend it. But even though she relishes the give and take, Dr. Blackburn admits to impatience at times with the questions some scientists have raised about one of her ventures. At issue is a lab test that measures telomeres, stretches of DNA that cap the ends of chromosomes and help keep cells from aging too soon. Unusually short telomeres may be a sign of illness, and Dr. Blackburn, thinks measuring them could give doctors and patients a chance to intervene early and maybe even prevent disease.
Other researchers have raised doubts about the usefulness of the measurement, which does not diagnose a specific disease. But Dr. Blackburn, a professor of biology and physiology at the University of California, San Francisco, says she has been convinced by a decade of data from her own team and others, linking short telomeres to heart disease, diabetes, cancer and other diseases, and to chronic stress and post-traumatic stress disorder. With studies that explore the connections among emotional stress, health and telomeres, she has delved into questions that she would have shied away from earlier in her career. The scope of her research has expanded from a tight focus on molecular biology to broader questions about the implications of her work for health and public policy.
Dr. Blackburn majored in biochemistry at the University of Melbourne and earned her doctorate at the University of Cambridge, where she became an expert in DNA sequencing. Her next stop after Cambridge, in 1975, was Yale.
Not much was known about telomeres at the time, and she began studying them at Yale in a one-celled organism, Tetrahymena, that she cheerfully calls “pond scum.” Telomeres are often compared to the plastic tips that keep the ends of shoelaces from fraying. Scientists had long suspected that telomeres protected the ends of chromosomes, but no one knew how. Each time a cell divides, its telomeres shorten, and if they get too short, the cell cannot divide any more. But somehow, in healthy cells, the telomeres were being rebuilt. Dr. Blackburn deciphered the structure, finding that telomeres consisted of six DNA units, repeated many times. She and a researcher at Harvard, Jack W. Szostak, determined that there must be an enzyme that keeps restoring the telomeres.
In the 1980s and 1990s, Dr. Blackburn’s interests widened. She describes herself as very visual, with a bent for analyzing graphs and the molecular patterns that emerge on X-ray films. A move to the University of California, San Francisco, in 1990, an institution with a medical school and a thriving world of clinical research, expanded her horizons. She began studying cancer, teaming her deep knowledge of cell biology with that of physicians who saw every day what mutated cells could do to patients. Her projects include studies in mice to find out whether blocking telomerase can fight cancer.
A little more than 10 years ago she began to collaborate with Elissa Epel, a psychologist at the university who studies chronic stress. One of their first projects involved mothers who were the main caregivers for children with chronic diseases. Compared with the mothers of healthy children, those with sick ones had shorter telomeres and less telomerase, and the longer they had been caring for the children, the shorter their telomeres were. The findings were similar in people taking care of spouses with dementia. Other studies have suggested that traumatic events early in life may have effects on telomeres and health that persist for decades. These studies, Dr. Blackburn said, have taken her far from her early days as a lab rat, to issues and segments of society that she considers neglected. She has also become curious about the physical and mental effects of meditation, learning one of the techniques herself. And she has wondered whether it does anything to telomeres.
In 2004, Dr. Blackburn gained a bit of notoriety – which she regarded as a badge of honor. Two years before, she had accepted an invitation to serve on President George W. Bush’s Council on Bioethics. But she supported research using embryonic stem cells, dissenting from the views expressed by the president, the council’s chairman and the group’s reports.
As data linking telomeres to stress and health accumulated, more people began asking if their telomeres could be measured. Dr. Blackburn began to think it reasonable to offer a test to the public and she helped found a company, Telome Health, in May 2010. The plan is to begin offering telomere tests to the public sometime in 2013. A doctor’s prescription will be required. The price has not yet been announced, but will be “competitive,” said the company’s president and chief scientific officer, Calvin Harley. Other companies with similar tests charge from $300 to $700. The test is nonspecific: it does not diagnose a particular disease.
Unusually short telomeres may indicate a health problem, and are a piece of information that should be factored into the bigger picture of a person’s health. “If you’re in the lowest percentile for your age group, you might really be interested in knowing why,” Dr. Blackburn said. “It’s something physicians would be interested in, for just that reason.” There are ways to protect telomeres, and maybe even lengthen short ones, Dr. Blackburn said. Exercise and a nutritious diet, losing excess weight and easing emotional stress may help. So, a low reading might be a wake-up call to take better care of oneself.
But some researchers are skeptical, arguing that the associations between short telomeres and illness do not prove cause and effect. Some scientists say there is so much individual variability in telomeres that it can be difficult to draw conclusions from the lengths in any one individual. Among those who have questioned the test is Dr. Greider, Dr. Blackburn’s fellow Nobel winner. However, her hope is that measuring telomeres will become part of a new direction in medicine, geared to what she calls “intercepting” disease.
Telomeres are structures on the tips of chromosomes that shorten as people age.
Promising Treatment for Lymphoma in Young People
Editor’s Note: We must not drop funding for NIH in the area of medical research. The following study makes it clear why this is true.
Primary mediastinal B-cell lymphoma mainly affects people from their teenage years to their early 30s. Many patients are cured with a combination of chemotherapy and radiation therapy. However, even with this treatment, about 20% of patients see their disease progress. Most patients receive radiation to the chest area, which can cause new cancers as well as damage to the heart. This is particularly a problem for young people because the risk of new cancers and heart disease continues to increase as they get older. Primary mediastinal B-cell lymphoma is also more common in women, who are at greater risk of developing breast cancer from radiation therapy to the chest.
According to an article published online in The New England Journal of Medicine (11 April 2013), patients with primary mediastinal B-cell lymphoma who received infusions of chemotherapy, but who did not have radiation therapy to an area of the thorax known as the mediastinum, had excellent outcomes. Until now, most standard treatment approaches for patients with this type of lymphoma have included radiation therapy to the mediastinum.
The results of this single arm trial, which followed 51 patients for a period of up to 14 years, was conducted by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. For the study, every patient in the trial received the drugs etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab in a regimen known as dose-adjusted EPOCH-R, or DA-EPOCH-R. This regimen uses infusion strategies in which doses of the drugs etoposide, doxorubicin, and cyclophosphamide are adjusted for greatest efficacy.
Fifty-one patients with untreated primary mediastinal B-cell lymphoma were included in this phase II study. The maximum tumor diameter was 11 centimeters. All but two patients achieved a complete remission with DA-EPOCH-R therapy, and none of the patients with a complete remission have developed a recurrent lymphoma. The two patients who did not achieve a complete remission received radiation and have also not had their tumors recur. There was no evidence of other diseases developing later on or cardiac toxic effects.
Global Economic Burden of Chagas Disease
Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. T. cruzi is commonly transmitted to humans and other mammals by an insect vector, the blood-sucking “kissing bugs” of the subfamily Triatominae (family Reduviidae), most commonly from species belonging to the Triatoma, Rhodnius, and Panstrongylus genera. The disease may also be spread through blood transfusion and organ transplantation, ingestion of food contaminated with parasites, and from a mother to her fetus.
The symptoms of Chagas disease vary over the course of an infection. In the early, acute stage, symptoms are mild and usually produce no more than local swelling at the site of infection. The initial acute phase is responsive to antiparasitic treatments, with 60–90% cure rates. After 4-8 weeks, individuals with active infections enter the chronic phase of Chagas disease that is asymptomatic for 60–80% of chronically infected individuals through their lifetime.
As Chagas disease continues to expand beyond tropical and subtropical zones, a growing need exists to better understand its resulting economic burden to help guide stakeholders such as policy makers, funders, and product developers. As a result, a study published in The Lancet Infectious Diseases (2013;13:342–348), developed a Markov simulation model to estimate the global and regional health and economic burden of Chagas disease from the societal perspective.
The Markov model structure had a 1 year cycle length and consisted of five states: acute disease, indeterminate disease, cardiomyopathy with or without congestive heart failure, megaviscera, and death. Major model parameter inputs, including the annual probabilities of transitioning from one state to another, and present case estimates for Chagas disease came from various sources, including WHO and other epidemiological and disease-surveillance-based reports. The authors calculated annual and lifetime health-care costs and disability-adjusted life-years (DALYs) for individuals, countries, and regions. They also used a discount rate of 3% to adjust all costs and DALYs to present-day values.
Results showed that on average, an infected individual incurs US$474 in health-care costs and 0.51 DALYs annually. Over his or her lifetime, an infected individual accrues an average net present value of $3,456 and 3.57 DALYs. Globally, the annual burden is $627.46 million in health-care costs and 806.170 DALYs. The global net present value of currently infected individuals is $24.73 billion in health-care costs and 29,385,250 DALYs. Conversion of this burden into costs results in annual per-person costs of $4,660 and lifetime per-person costs of $27,684. Global costs are $7.19 billion per year and $188.80 billion per lifetime. A substantial proportion of the burden emerges from lost productivity from cardiovascular disease-induced early mortality.
More than 10% of these costs emanate from the USA and Canada, where Chagas disease has NOT been traditionally endemic.
According to the authors, the economic burden of Chagas disease is similar to or exceeds those of other prominent diseases globally (e.g., rotavirus $2.0 billion, cervical cancer $4.7 billion). Even in the USA where Chagas disease has not been traditionally endemic, an economic argument is suggestive for more attention and efforts towards the control of Chagas disease.
Individual- vs. Group-Based Financial Incentives for Weight Loss: A Randomized, Controlled Trial
Background: Data on the effectiveness of employer-sponsored financial incentives for employee weight loss are limited. As a result, a study published in the Annals of Internal Medicine (2013;158:505-514) was performed to test the effectiveness of 2 financial incentive designs for promoting weight loss among obese employees.
The study was a randomized, controlled clinical trial including 105 employees with a body mass index between 30 and 40 kg/m2. The primary outcome measure was weight loss after 24 weeks. Secondary outcome measures included changes in behavioral mediators of weight loss at 36 weeks. The intervention included 24 weeks of monthly weigh-ins (control group; n=35); individual incentive, designed as $100 per person per month for meeting or exceeding weight-loss goals (n=35); and group incentive, designed as $500 per month split among participants within groups of 5 who met or exceeded weight-loss goals (n=35).
Results showed that group-incentive participants lost more weight than control participants (mean between-group difference, 4.4 kg; P <0.001) and individual-incentive participants (mean between-group difference, 3.2 kg; P=0.008). Twelve weeks after incentives ended and after adjustment for 3-group comparisons, group-incentive participants maintained greater weight loss than control group participants (mean between-group difference, 2.9 kg; P=0.016) but not greater than individual-incentive participants (mean between-group difference, 2.7 kg; P=0.024).
According to the authors, group-based financial incentive was more effective than an individual incentive and monthly weigh-ins at promoting weight loss among obese employees at 24 weeks.
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FDA Budget Requests $4.7 Billion to Ensure Safety of Food Supply and to Modernize Medical Product Safety
The FDA is requesting a budget of $4.7 billion to protect and promote the public health as part of the President’s fiscal year (FY) 2014 budget. Industry user fees would fund 94% of the proposed budget increase, including new fees to support the landmark Food Safety Modernization Act (FSMA) and strengthen the FDA’s ability to oversee imported food. The remainder of the budget increases would support programs which are necessary to preserve the safety of medical products and meet the agency’s growing duties. Recognizing the need for fiscal constraint, the budget includes spending cuts in several areas, including a $15 million decrease in budget authority for human drug, biologics, and medical device programs.
Highlights of the FDA FY 2014 budget include:
Transforming Food Safety: +$295.8 million ($252.4 million in User Fees / $43.4 million in budget authority) above the FY 2012 level will bolster the FDA’s efforts to build a strong, reliable food safety system. Most of these funds are needed to support implementation of the FSMA, which provides authorities and mandates for the FDA to build a modern, prevention-focused domestic and imported food safety system to protect the health of American consumers. The budget proposes a food facility registration and inspection fee and a food importer fee. The FDA is also proposing new user fees to support its cosmetic and food contact substance notification programs. The President’s budget proposes a fee to be paid by food importers that would both improve the safety of the food supply as well as ensure the smooth and predictable entry of safe foods into the United States, thus enhancing trade by domestic and overseas trading partners.
White Oak Consolidation: +$17.9 million above the FY 2012 level will support the outfitting and required certification and operation of the Life Sciences-Biodefense Complex (the FDA’s White Oak headquarters in Silver Spring, Md.) to carry out cutting-edge research to ensure that the FDA is providing the best possible oversight over its regulated products to protect the American public. This is a cornerstone of the FDA’s effort to modernize regulatory science and promote medical product innovation.
Food and Drug Safety Inspections in China: +$10 million above the FY 2012 level will support the FDA’s capacity to detect and address the risks of products and ingredients manufactured in China and to help assure that these products do not result in harm to Americans.
Medical Countermeasures (MCM) Initiative: +$3.5 million above the FY 2012 level will help meet America’s national security and public health requirements for MCM readiness. The additional resources in FY 2014 will support science and partnerships to improve MCM development timelines and the success rates for MCMs.