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The modified bacteria themselves are relatively harmless, but their unmodified counterparts produce poisons that have killed some humans and cattle when introduced into the bloodstream. "It is not difficult to kill cancer cells. The challenge is killing them while sparing normal cells," says Bert Vogelstein, M.D., professor and co-director of the Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center. The bacteria's cancer-killing effects were first discovered five years ago by the Johns Hopkins team who noticed the germ's ability to grow and spread in the oxygen-poor core of mouse tumors and the blackened scars signaling that most of the cancer cells had been destroyed. Normal surrounding cells were largely unaffected. But the bacteria failed to kill cancer cells at the still oxygen-rich edge of the tumors. In response, the Johns Hopkins team added specially packaged chemotherapy to the bacterial attack speculating that certain properties of the bacteria would improve the drug's effectiveness, according to Shibin Zhou, M.D., Ph.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center. The combo approach temporarily wiped out both large and small tumors in almost 100 mice and permanently cured more than two-thirds of them. The likely explanation for the greater cancer cell kill by the combination treatment is that the bacteria expose the tumors to six times the amount of chemotherapy than is usually the case by improving the breakdown and dispersal of the chemotherapy's fatty package at the tumor site. The investigators repeated experiments using two packaged chemotherapy drugs -- doxorubicin and irinotecan -- and observed similar tumor-killing effects of both when used in combination with the bacteria. "Packaged" cancer drugs currently are available in microscopic fatty capsules called liposomes which gravitate to tumors because they are too large to fit through the skins of tightly woven blood vessels surrounding normal tissue and small enough to get through tumor vasculature. Combining C.novyi-NT and liposomes filled with chemotherapy seems to have its synergistic effect on tumors owing to the presence of an enzyme found lurking in C. novyi-NT cultures, which Ian Cheong, Ph.D., in the Vogelstein lab dubbed liposomase. It destroys fatty membranes and may disrupt the outer layer of liposomes releasing their drug contents. "Drugs contained in these ‘Trojan horse' compartments are specifically released at the tumor site by the C-novyi-NT bacteria which may improve the effectiveness and safety of the therapy," says Cheong, who is the lead author of the study. The scientists note that liposomase could be used in a variety of other targeted therapies besides the bacteria combination. Such approaches could include attaching liposomase to antibodies that have an affinity for specific tumors or adding its DNA code to gene therapy. As many drugs can be packaged within liposomes, the investigators say the approach could have general utility. In a companion study, the Johns Hopkins team decoded the entire C.novyi-NT genome, which Zhou says "was instrumental in identifying liposomase and will help improve our bacterial-based therapies." Preliminary safety tests of injected C. novyi-NT alone are under way in a small number of cancer patients. The research was funded the Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Foundation, Miracle Foundation, and the National Institutes of Health. Co-authors include Xin Huang, Chetan Bettegowda, Luis A. Diaz., Jr., and Kenneth W. Kinzler at the Johns Hopkins Kimmel Cancer Center.   MILLIONS WITH ARTHRITIS MAY BENEFIT FROM BONE LOSS DRUG   People taking a widely used medication to strengthen fragile, aging bones may also be protecting their joints, according to a recent study led by Johns Hopkins rheumatologist Clifton Bingham, M.D. Researchers began to wonder if risedronate might be used to treat osteoarthritis after noticing that the drug, and other compounds in the same class of drugs, not only slowed joint damage in animals, but also reduced cartilage-irritating bone lesions in humans. For two years, an international team of investigators studied 2,483 arthritic men and women, from both the United States and Europe. All of those enrolled in the study had a loss in the cartilage that cushions the knee joint, a hallmark symptom of osteoarthritis. Bingham and his team said study participants were given either a placebo or risedronate at a range of doses, including the standard doses normally prescribed to treat bone loss. The amount of cartilage detected in their knees was measured by X-ray analysis at the one- and two-year marks. Blood tests were also used to check for a marker of cartilage breakdown known as CTX-II. CTX-II is released in the bloodstreams of people with osteoarthritis when cartilage begins to fray. How fast and to what degree cartilage breaks down can be approximated by levels of CTX-II. "The blood tests revealed not only that risedronate stabilized bone loss, but also that it was most likely slowing the breakdown of cartilage, too" says Bingham. Bingham emphasizes that X-rays failed to show any dramatic visible changes in the structure of the joints with risedronate compared to a placebo: however, the numbers of patients exhibiting significant progression of the disease were few in all treatment groups. A great challenge now is identifying the risk factors for joint deterioration in osteoarthritis, adds Bingham. In the United States, where an estimated 25 million people have osteoarthritis and 44 million have osteoporosis, participants in the study group taking risedronate experienced a noticeable drop in their CTX-II levels. Patients taking the drug at normal levels and at higher than usual doses given for comparison experienced similar slowdowns in cartilage decline, without significant adverse side effects. Those in the placebo group, however, experienced increases in CTX-II levels, suggesting that their cartilage was deteriorating faster than that in those taking the drug. "We are not recommending that everyone with arthritis run out and get a prescription for these kinds of drugs, nor are we suggesting at this time that doctors use risedronate as an arthritis treatment," cautions Bingham. "But what we can say now is that drugs affecting bone turnover need to be further evaluated for their potential effects as arthritis therapies." The blood test changes seen in the study would suggest that people already taking bone strengthening drugs may be simultaneously helping their joints, concludes Bingham. NOTE: Dr. Bingham has received consulting fees from Proctor & Gamble Pharmaceuticals, the makers of Actonel, the brand name for risedronate. Additionally, several other members of his research team have received consulting fees from other pharmaceutical companies.   SOY PROTEIN STUDY GENERATES NEW FINDINGS IN CHOLESTEROL REDUCTION, METABOLIC SYNDROME, AND CLINICAL TRIALS RECRUITMENT   The Beneficial Effects of Soy Trial (BEST), a Baltimore-based randomized controlled study of dietary soy, has yielded an array of results pertaining to cholesterol reduction, metabolic syndrome, and recruitment for clinical trials. The multi-disciplinary study team was led by Johns Hopkins University School of Nursing (JHUSON) researcher and lead investigator Jerilyn K. Allen, ScD, RN. Allen and co-authors report that among their BEST study group -- 216 healthy postmenopausal African American and white women with moderately elevated low-density lipoprotein (LDL) cholesterol levels -- those who received isolated soy protein containing isoflavones experienced a significant decrease in total cholesterol, LDL cholesterol, and lipoprotein particles. Noting that because lipoprotein levels often increase as a consequence of menopause, Allen cautions that while soy protein alone will not lower cholesterol with the same effectiveness as medications, "the modest effects of soy protein on LDL cholesterol and LDL particle number may be beneficial for heart health in postmenopausal women who do not require statins or other medications to control their levels." In an American Heart Association meeting, Allen and JHUSON co-authors Sarah Szanton, Kathleen Lindenstruth, and Carol Curtis reported additional BEST study findings on factors associated with cardiovascular disease (CVD). The investigators reported on their evaluations of women in the study with metabolic syndrome MS) a clustering of at least three CVD risk factors: high blood pressure, high triglycerides, low levels of HDL cholesterol (good cholesterol), high glucose, or abdominal obesity (large waist measurement). When compared to women in the study without the syndrome, those with MS had lower levels of high-density lipoprotein cholesterol and higher levels of triglycerides without significant differences in total cholesterol. However, there were significant differences in major lipoprotein subclass measures, showing that women with MS had smaller mean LDL size, higher LDL participle concentration, and smaller mean HDL size; all factors putting them at increased risk for CVD. During the study, investigators also compiled data on recruitment into the clinical trial. Published in Ethnicity and Disease, Lindenstruth's analysis shows that African American and white women differed significantly in their response to various forms of mass media and personalized techniques employed to recruit participation in the clinical trial. The most effective mechanism for recruiting African American women was direct mail, followed by radio; newspapers were less effective. Conversely, white women responded best to newspaper ads, followed by direct mail; and radio was less effective. These strategies were more effective than the personalized techniques -- health fairs, provider referrals, newsletters and churches. The BEST study was funded by the National Heart Lung and Blood Institute to determine the effects of soy on lipids, lipoproteins and lipoprotein subclasses in a sample of African-American and white postmenopausal women. The secondary aims of the study were to assess the impact of soy on menopausal quality of life, including menopausal symptoms, and to examine racial/ethnic differences in quality of life, acceptability, and adherence to the soy supplementation.   CHOCOLATE "OFFENDERS" TEACH SCIENCE A SWEET LESSON   Some "chocoholics" who just couldn't give up their favorite treat to comply with a study to test blood stickiness have inadvertently done their fellow chocolate lovers - and science - a big favor. Their "offense," say researchers at Johns Hopkins led to what is believed to be the first biochemical analysis to explain why just a few squares of chocolate a day can almost halve the risk of heart attack death in some men and women by decreasing the tendency of platelets to clot in narrow blood vessels. "What these chocolate 'offenders' taught us is that the chemical in cocoa beans has a biochemical effect similar to aspirin in reducing platelet clumping, which can be fatal if a clot forms and blocks a blood vessel, causing a heart attack," says Diane Becker, M.P.H., Sc.D., a professor at the Johns Hopkins University's School of Medicine and Bloomberg School of Public Health. Becker cautions that her work is not intended as a prescription to gobble up large amounts of chocolate candy, which often contains diet-busting amounts of sugar, butter and cream. But as little as 2 tablespoons a day of dark chocolate - the purest form of the candy, made from the dried extract of roasted cocoa beans - may be just what the doctor ordered. Researchers have known for nearly two decades that dark chocolate, rich in chemicals called flavonoids, lowers blood pressure and has other beneficial effects on blood flow. The latest Johns Hopkins findings identified the effect of normal, everyday doses of chocolate found in ordinary foods, unlike previous studies that found decreased platelet activity only at impractically high doses of flavonoids equivalent to eating several pounds of chocolate a day. "Eating a little bit of chocolate or having a drink of hot cocoa as part of a regular diet is probably good for personal health, so long as people don't eat too much of it, and too much of the kind with lots of butter and sugar," says Becker. In the study, 139 people Becker - whom Becker somewhat tongue in cheek calls "chocolate offenders" - were disqualified from a much larger study looking at the effects of aspirin on blood platelets. Shortly before aspirin dosing began for the subjects, they were told to stay on a strict regimen of exercise and to refrain from smoking or using foods and drinks known to affect platelet activity. These included caffeinated drinks, wine, grapefruit juice - and chocolate. The non-compliers - who admitted to eating chocolate - were a diverse group who got their flavonoid "fix" from a variety of sources, including chocolate bars, cups of hot cocoa, grapes, black or green tea, and strawberries. And while they were excluded from the aspirin study, Becker and her team scoured their blood results for chocolate's effect on blood platelets, which the body recycles on a daily basis. When platelet samples from both groups were run through a mechanical blood vessel system designed to time how long it takes for the platelets to clump together in a hair-thin plastic tube, the chocolate lovers were found to be less reactive, on average taking 130 seconds to occlude the system. Platelets from those who stayed away from chocolate as instructed clotted faster, at 123 seconds. In another key test of urine for waste products of platelet activity, primarily urinary thromboxane, scientists found that chocolate eaters showed less activity and waste products on average, at 177 nanograms per millimol of creatinine, versus an average of 287 nanograms per millimol of creatinine in the group that abstained. Participants ranged in age from 21 to 80; 31 percent were black and the rest were white. In total, more than 200 different tests of platelet reactivity were performed and analyzed in the study. Because whole blood contains other cells that affect platelet aggregation, testing was repeated using a purified version of test samples made up of strictly platelet-rich plasma. None of the "offenders" had previous histories of heart problems, such as a heart attack, but all were considered to be at slightly increased risk of heart disease because of family history. Fifty percent of women participants were postmenopausal. "These results really bring home the point that a modest dietary practice can have a huge impact on blood and potentially on the health of people at a mildly elevated risk of heart disease," says study co-author Nauder Faraday, M.D., an associate professor at Johns Hopkins. "But we have to careful to emphasize that one single healthy dietary practice cannot be taken alone, but must be balanced with exercise and other healthy lifestyle practices that impact the heart." Besides Becker and Faraday, other investigators in this research were Lisa Yanek, M.P.H.; Taryn Moy, M.S.; and Lewis Becker, M.D.   NEW HUMAN STEM CELL CENTER AT JOHNS HOPKINS EXPECTED TO SPEED RESEARCH AND KEEP IT SAFE   In a novel effort to simplify and speed up safe human stem cell research, Johns Hopkins has set up a "one-stop shop" to preserve, create, supply and test high-quality cell lines for its own researchers now and the greater scientific community later. The privately funded Stem Cell Resource Center, housed for now within the School of Medicine's Institute for Cell Engineering on the East Baltimore campus, offers streamlined and centralized handling of cell lines and requests to use them and is expected to cut wait times and paperwork substantially, according to Chi V. Dang, M.D., Ph.D., the school's vice dean for research and head of the institute, known as ICE. In tandem with the opening of the new center, Johns Hopkins appointed an eight-person Embryonic Stem Cell Research Oversight (ESCRO) committee modeled on guidelines set forth in 2005 by the National Academies. Similar to institutional review boards that oversee the safety of human subjects in research, the ESCRO committee's charge is to ensure that all human stem cell experiments conducted at the university are safe. "It's frankly astonishing that no other place has done the much-needed, head-to-head comparison of the existing stem cell lines to fully describe them and make sure they're safe to use," says Dang. "This isn't the 'sexy' part of stem cell work, but it's critical because this research aims at developing stem cell treatment for use in people, and ESCRO is going to make sure to every extent possible that such use at Hopkins is safe." The center and ESCRO will call on Johns Hopkins experts to screen all cell lines for alterations or mutations that might compromise their quality or signal danger. Last year, a team led by researchers at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins reported that human embryonic stem cell lines accumulate changes in their genetic material over time. Cells grown in the lab longer were worse off, containing the wrong number of chromosomes, changes in the marks that control genes, or changes in the DNA sequence. While the precise effects of these changes aren't known, some resemble those seen in cancer cells. Whether the changes affect the stem cells' abilities to become other cell types also is unknown. Within the center, experts in the study of genes and their functions (genomics) will develop molecular toolkits for turning on or off genes that coax stem cells to develop into specific cell types, and experts in microscope imaging will create and test better ways to mark the cells so that they can be observed and followed as they grow and develop. "We're convinced that such services will bring a stunning level of confidence and security to stem cell research at Hopkins, so much so that scientists will be able to work more quickly," Dang says. With plans to apply for funds from Maryland's new stem cell initiative, Dang adds, the center hopes to open its services to non-Hopkins scientists in the state and more widely next year. Beyond researcher convenience and safety, centralization of services within the center should mean economies of scale that will lead to better use of dollars and time, Dang notes. "These are core operations that can't always be done by a single lab, and now that lab doesn't have to reinvent every wheel to do important work," he says. "We know of many researchers who would like to venture into stem cell science but don't in great measure because of the immense bureaucratic burden of paperwork required to gain access to individual cell lines by contract or material transfer agreements," he says. "The center will do all that for the entire university, so that as far as any individual investigator can tell, it will be free access." With start-up support from a small portion of a $100 million anonymous gift to The Johns Hopkins University earlier this year, the center first will store a collection of adult and embryonic stem cell lines, some approved for studies that have federal funding and some not. The center also will keep tabs on the funding used to support research on all the cells it provides to ensure compliance with federal laws. Human embryonic stem cells are obtained from extra embryos created during in vitro fertilization. Because the cells can become any type of cell in the body, they may one day treat or cure diseases such as Parkinson's disease or type I diabetes. As the new center ramps up its services, the new ESCRO committee will set university-wide standards on experiments performed at Johns Hopkins under the leadership of Jeremy Sugarman, M.D., professor in Johns Hopkins' Berman Bioethics Institute, and Carol Greider, Ph.D., the Daniel Nathans Professor and director of molecular biology and genetics in the Institute of Basic Biomedical Sciences and recent winner of the Lasker Award for her work on chromosomes.   DIABETES NOT THE SAME FOR ALL AGES   Elderly persons who were diagnosed with diabetes during middle age (40-64 years) and those diagnosed later in life (over 65 years) comprise two distinct groups, according to new research from the Johns Hopkins Bloomberg School of Public Health. The study, published in Diabetes Care, found that these two age groups have different disease burdens and may require different treatment goals. "The number of individuals aged 65 or older in the U.S. is increasing markedly and diabetes is a growing problem in this population. In addition, people are living to much older ages with high quality of life, which speaks to the need for more aggressive treatment among elderly persons with diabetes," said Elizabeth Selvin, PhD, MPH, lead author of the study and a postdoctoral fellow in the Bloomberg School of Public Health's Department of Epidemiology. The study authors analyzed 1999-2002 data for 2,809 elderly persons in order to present a nationally representative estimate of the prevalence of diabetes among elderly persons in the general U.S. population. The data were taken from the National Health and Nutrition Examination Survey (NHANES), an on-going cross-sectional survey of the civilian, non-institutionalized U.S. population. The authors report that 15 percent of the U.S. population aged 65 years or older, had been diagnosed with diabetes, a figure that represents approximately 5.4 million individuals. In addition, 6.9 percent of the U.S. population aged 65 years or older (2.4 million individuals) have undiagnosed diabetes and are unaware of their condition. Elderly persons with middle-age-onset diabetes were more likely to have retinopathy, reflecting the cumulative damage of high glucose levels over the course of many years. They also had much worse glycemic control. In contrast, elderly persons with newly diagnosed diabetes had a comparable burden of cardiovascular disease but required less aggressive treatment to reach blood pressure and cholesterol treatment goals. "The two types of elderly persons with diabetes have distinct characteristics, including different burdens of disease," said Selvin. "Elderly people with diabetes are a heterogeneous group and doctors may need to consider different treatment goals for these two groups in clinical practice." "The Burden and Treatment of Diabetes in Elderly Individuals in the U.S." was co-authored by Elizabeth Selvin, Josef Coresh and Frederick L. Brancati. Elisabeth Selvin was supported by a grant from the National Heart, Lung, and Blood Institute.