Research Notes

Updated 11:00 AM September 9, 2004

Research Notes

Scientists find common virus in human prostate tissue

Chances are excellent that your urinary tract is home to a pathogenic organism called the human BK virus. Most of the time, the virus lurks quietly in the kidneys without causing problems.

Many scientists think abnormal prostate cell changes like those shown here could be the first step in the transition to prostate cancer (top). Benign prostate tissue (middle) and cancerous prostate tissue (above). Professor Michael Imperiale (below) directed the team of scientists.

But in people with a depressed immune system—especially those who have just received a kidney transplant—the virus can cause serious kidney and bladder disease.

Now, research by scientists in the Medical School suggests the intriguing possibility that this common virus also may play a role in prostate cancer—the second-leading cause of deaths from cancer in American men.

A team of scientists directed by Michael Imperiale, professor of microbiology and immunology, has found DNA and proteins from the BK virus in prostate tissue with abnormal cell changes. Called atrophic lesions, these changes can be the first step in a series of progressive cell changes leading to prostate cancer.

"Other studies have detected DNA from the BK virus in prostate cancer cells, but this study is the first to pinpoint the location of viral protein expression to one precursor stage in the development of prostate cancer, and to a specific location within prostate cells," Imperiale says.

Results from the study, published July 19 in the advance online edition of the journal Oncogene, are available at http://www.nature.com/onc/
journal/vaop/ncurrent/. Scientists analyzed 21 samples of prostate tissue for the study; tissue samples were obtained from the Tissue Procurement Core at the Comprehensive Cancer Center. Scientists also removed DNA from the samples for sequencing and identification in U-M's DNA Sequencing Core facility.

"The development of cancer is a multi-step process," Imperiale says. "Expression of BK viral protein may be just one step among several genetic and environmental factors. We are not saying that BK virus causes prostate cancer, but our results do suggest that the virus plays a role in the transition from normal to uncontrolled growth of prostate cells."

Dweepanita Das, a post-doctoral fellow, was first author on the paper. Dr. Rajal Shah, a clinical assistant professor of pathology and urology in the Medical School, was co-author. The study was funded by a grant from the U.S. Army's Medical Research and Material Command, Department of Defense.
—Sally Pobojewski, Medical School Communications

Buying stocks? Don't listen to investment banks

Stocks purchased at the recommendation of independent research firms outperform those recommended by investment banks, according to a Business School researcher.

When it comes to selling, though, investment banks did a better job than the independents.

A new study co-authored by
Reuven Lehavy, assistant professor of accounting, found that from 1996 to mid-2003, buy recommendations issued by securities firms with no investment banking business outperformed the buys issued by analysts at investment banks by an average of about 8 percentage points annually.

In contrast, hold-and-sell recommendations from investment banks outperformed (on the downside) those of the independent research firms by 4.5 percentage points annually.

According to Lehavy and colleagues Brett Trueman of the University of California, Los Angeles, and Brad Barber of the University of California, Davis, investment bank buy recommendation underperformance was concentrated in the period that followed to the NASDAQ market peak (March 10, 2000). During this time, stocks recommended by independent firms outperformed stocks recommended by investment banks by an average of 17 percent annually.

More strikingly, during this period buys recommended by investment banks following equity offerings underperformed those of independent research firms by almost 22 percent annually, they say.

"These results suggest that the underperformance of investment bank buy recommendations was at least partly due to a reluctance to downgrade stocks whose prospects dimmed during the early 2000's bear market," Lehavy says, noting that the findings mirrored those made by the Securities and Exchange Commission (SEC) in its recent Global Analyst Research Settlement. Under the settlement, the SEC and other regulators mandated that 10 of the largest investment banking firms provide independent research to their clients.
—Bernie DeGroat, News Service

Goals unlikely to protect Gulf of Mexico shrimp industry

The current federal plan to reduce the "dead zone" in the Gulf of Mexico may not be enough to protect the region's half billion dollar a year shrimp industry, research shows.

Researchers from U-M, Louisiana State University and Ann Arbor-based firm Limnotech Inc. used three different models to analyze oxygen depletion. They also sought to determine whether the expanded dead zone is human-caused and if the goal of a 30 percent reduction in nitrogen load will be sufficient to reduce the zone to below 5,000 square kilometers, as agreed to by federal, state and tribal leaders in 2001.

The dead zone is a "hypoxic region," an area where water lacks sufficient oxygen to sustain most marine life. In the Gulf of Mexico it is caused by excess nitrogen—largely runoff from Midwest agriculture, says Donald Scavia, director of the Michigan Sea Grant and professor in the School of Natural Resources and Environment.

Scavia's paper, published in the June edition of the journal Estuaries, found that the 30 percent reduction in nitrogen load likely will not shrink the dead zone to the desired 5,000 square kilometers. According to the paper, the nitrogen load must be reduced by 40 to 45 percent to achieve that reduction in most years. It is important to reduce the size of the dead zone in the Gulf, Scavia says, because the area is a key habitat for shrimp and other fin and shellfish.

Comparing the results of three models also confirmed anecdotal and sparse historic data indicating that large-scale hypoxia did not occur before the mid-1970s and supports the notion that tripling the nitrogen load during the past 50 years has led to the heightened Gulf of Mexico hypoxia problem.

Confidence in the model analysis was bolstered this year as the operational ecological forecast from the

National Oceanic and Atmospheric Administration (NOAA), based on Scavia's model, predicted this summer's dead zone to be 5,400 square miles. Measurements from the NOAA-supported surveys by the Louisiana Universities Marine Consortium documented the zone to be 5,800 square miles, or about the size of Connecticut.
—Laura Bailey, News Service

Tumor cell levels in blood predict success of breast cancer treatment

Women with advanced breast cancer who have a higher number of tumor cells circulating in their blood progress more rapidly and die sooner than women with fewer of these cells, according to a study by researchers from the Comprehensive Cancer Center (CCC) and other cancer centers throughout the country.

These researchers determined that about half of 177 women in the study whose breast cancer had metastasized, or spread, and who were starting a new treatment had elevated levels of circulating tumor cells in their blood system. Investigators defined an elevated level as five or more tumor cells in a sample of blood.

Of those women, 30 percent still had higher numbers of circulating tumor cells three to five weeks after beginning a new treatment, and their cancer progressed very rapidly compared to women whose tumor cell levels dropped during that time or who never had elevated circulating cell levels. The study was performed using a newly developed technology called CellSearch that isolates and characterizes these cells. Results appeared in the Aug. 19 New England Journal of Medicine.

"Identifying the number of circulating tumor cells in patients with metastatic breast cancer, especially at the time of their first follow-up after starting new therapy, may provide an early, reliable indication of whether that therapy will be successful," says principal investigator and senior study author Dr. Daniel Hayes, clinical director of the Breast Oncology Program at CCC and professor of internal medicine at the Medical School.

Currently, to determine if a therapy is effective, patients often must wait three to four months after beginning the treatment and then undergo a series of tests, including bone scans and X-rays. If the technique used in this study is proven effective, doctors could determine within several weeks if the therapy is working, with only a routine blood draw from the patient.

The study was funded by Immunicon Corp., from which Hayes has received grants and for which he has served as a consultant. Other authors were from MD Anderson Cancer Center, Cleveland Clinic, Duke University, University of Arizona and Immunicon Corp.

For more information on metastatic breast cancer, call the Cancer AnswerLine at (800) 865-1125 or visit http://www.cancer.med.umich.edu/learn/breastmet.htm.
—Nicole Fawcett, UMHS Public Relations

U.S. economy: Solid, but not spectacular, through 2006

Economic growth in the United States will be steady during the next two years, but not outstanding, say U-M economists.

After a slowdown in the second quarter, real Gross Domestic Product growth will edge upward and remain in the 3.25-3.5 percent range during the latter half of this year and during much of 2005 and 2006, with solid growth in household consumption and robust business spending, they say.

"Economic growth picks up in the second half of 2004, following what Alan Greenspan termed the 'soft patch' of this spring, but oil prices remain above earlier expectations and rising interest rates keep output growth near its trend rate through 2006," says Saul Hymans, professor of economics. "However, that should be sufficient for job growth to rebound from the sluggish pace of June and July."

In their annual mid-year forecast update of the U.S. economy, Hymans and colleagues Joan Crary and Janet Wolfe predict employment growth of more than 800,000 jobs in the second half of this year and job gains of about 1.9 million in each of the next two years.

While unemployment is expected to decline gradually from 5.6 percent in 2004 to 5.4 percent next year and to 5.2 percent in 2006, inflation and interest rates will continue to rise, the forecast shows.

For more information about the U-M forecast—which is based on the Michigan Quarterly Econometric Model of the U.S. Economy and compiled by the U-M Research Seminar in Quantitative Economics—visit http://www.umich.edu/~rsqe.
—Bernie DeGroat, News Service

Parents' anti-asthma efforts may miss the mark

Parents of children with asthma are making many efforts to clear their homes of substances that could trigger their children's symptoms, but the steps they take aren't always the ones that could do the most good, a U-M study finds. And many parents don't take other steps that are known to help.

Only half of the 1,788 asthma-proofing steps taken by parents of 896 asthmatic children in the study were likely to work. The other half were unproven, unlikely to be helpful against the child's individual triggers or, in a few cases, potentially harmful.

The study's authors say their findings indicate a tremendous need for doctors and other health care providers to educate parents about what might trigger asthma symptoms and attacks, and about the most effective steps they can take to reduce their child's exposure to those substances.

The research results, based on in-depth interviews, were published in the August issue of the Journal of Allergy and Clinical Immunology by a team from the U-M Health System, C.S. Mott Children's Hospital, and the School of Public Health (SPH).

Most often, parents reported taking steps to control their child's exposure to dust, dust mites and animals, and many said they were using special filters on ventilation systems and vacuum cleaners.

Some parents reported buying a mattress cover for a child whose asthma is triggered by plant pollen, but not shutting windows to keep pollen out of the house. Even worse, one-quarter of the parents reported that someone in the same household as the asthmatic child smoked, but didn't report that there had been any effort to address this issue.

The lead author was pediatrician Dr. Michael Cabana, associate professor of general pediatrics at the Medical School, and co-author was pediatric pulmonologist Dr. Toby Lewis, assistant professor of pediatrics in the Medical School.

The results came from the baseline parent interviews of U-M's Physician Asthma Care Education (PACE) project, which is led by SPH Dean Noreen Clark and funded by the Robert Wood Johnson Foundation. Clark is senior author on the paper.
—Kara Gavin, UMHS Public Relations

In gene regulation, small is beautiful

Chemists have used small molecules to take a big step forward in controlling gene activity.

Scientists have been trying for some time to develop molecules that mimic natural regulators of gene expression. These natural regulators, called transcription factors, prompt particular genes to be active or to stay quiet. Their role is crucial, because errors in gene regulation can lead to diseases ranging from diabetes to cancer. Creating synthetic versions, known as artificial transcription factors (ATFs), could help scientists probe gene regulation and perhaps lead to new treatment approaches.

Both natural transcription factors and their artificial counterparts typically have two essential parts: a DNA-binding domain that homes in on the specific gene to be regulated, and a regulatory domain that attaches itself to the cell's machinery and activates or represses the gene.

Recently, assistant professor of chemistry Anna Mapp and coworkers designed small molecules that mimic in a general way the features of natural transcriptional activators. In this research, published online in the Journal of the American Chemical Society last month, small molecule artificial activation domains developed in Mapp's lab were as effective as a natural activation domain at turning on genes.

Small molecules have great advantages as artificial gene regulators, says Mapp, who discussed the work last month at a meeting of the American Chemical Society. They are less likely than larger molecules to be degraded, and they should be easier to introduce into cells—features that would be critical if ATFs are to be used in treating disease.

Next, Mapp's group plans to investigate exactly how their artificial activators work.

"We haven't rigorously proven that they function by the same mechanism as natural activators, but they seem to be quite analogous," she says. The researchers also will try attaching their activators to different DNA-binding domains to see if that affects their activity.
—Nancy Ross-Flanigan, News Service

Strep disrupts blood clotting to infect humans

U-M researchers have captured a glimpse of the endless arms race between infectious agents and the human immune system in a bacterium that uses a mimic of a human blood-clotting enzyme to advance its infection.

Streptococcal bacteria use an enzyme called streptokinase to block the blood clotting response and allow themselves to move more freely around the human host's circulatory system. The molecule is so specific it only works on humans, not on other animals.

"The theory is that, as bacteria cause a local infection and begin to grow, the clotting system produces clots in the blood vessels around the infection, closing the highways that the bacteria would use to spread," says Dr. David Ginsburg, the James V. Neel Distinguished University Professor of Internal Medicine and Human Genetics and a research professor in the Life Sciences Institute. He also is a Howard Hughes Medical Institute investigator.

"The bacterial streptokinase enzyme bypasses this blood-clotting system by causing the blood clot to dissolve so the bacteria can spread," Ginsburg says.

Streptokinase secreted by group A streptococcus works by activating the human form of the enzyme plasminogen, which routinely dissolves blood clots in the body.

The findings suggest that subtle variations in plasminogen genes among humans may explain why some people are more susceptible to strep infections than others. The research, which was published in the Aug. 26 issue of the journal Science, also included colleagues at Lund University in Sweden.
—Karl Leif Bates, News Service

Let them fail: Encourage employees to experiment

Rewarding employees who repeatedly try new things and fail leads to more innovation and bigger long-term successes, according to new research.

Innovation is a kind of Holy Grail for management but when organizations are inconsistent in their support for experimentation or scrutinize workers too closely, they actually inhibit innovation, the research found.

"To survive, organizations need to experiment constantly with new ideas and not get stuck doing the same old routine," says Fiona Lee, a psychology and business professor who is an expert on organizational behavior. "We've been looking at why some people experiment and others don't. We find that when managers send mixed messages, people get scared and actually stop trying out new ideas."

Members of organizations who fear their mistakes, errors and failures will be held against them lack "psychological safety" and become fearful of taking risks or experimenting, Lee concludes in the journal Organization Science.

Yet innovation is at least partially based on accumulated failure, with crucial developments from the light bulb to vaccines being developed only after years of constant trial-and-error experimentation.

Telling people to experiment but monitoring and punishing their mistakes when they do so lowers psychological safety and increases fear, creating discouraging conditions, Lee says.
—Joseph Serwach, News Service

Higher stroke risk found in Mexican Americans

Mexican Americans have a far higher chance of suffering a stroke than non-Hispanic whites, according to a study led by a U-M stroke specialist.

And, according to a second study published by the same team, the difference doesn't appear to be related to Mexican Americans' higher incidence of diabetes, which had been thought to raise their risk of a certain type of stroke.

It's the first time that the stroke gap between the two groups has been demonstrated, and the studies have far-reaching implications for educating Mexican Americans about preventing strokes and acting quickly when one strikes. It also raises questions about factors that might be contributing to the difference in risk.

The two studies, published in the Aug. 15 issue of the American Journal of Epidemiology (AJE) and the Aug. 10 issue of Neurology, come from an in-depth population-based project funded by the National Institutes of Health and called BASIC, for Brain Attack Surveillance in Corpus Christi.

Lead author Dr. Lewis Morgenstern, who directs the U-M Stroke Program and the BASIC study, calls the results a "wake-up call to the country" about the third-leading cause of death and leading cause of disability in the nation. Mexican Americans make up two-thirds of Hispanics, the nation's largest minority group.

"This is a best-case scenario population of Mexican Americans, who have been in this country for several generations and have few cultural and language barriers to getting medical care," says Morgenstern, an associate professor of neurology at the Medical School. "If their risk of stroke is this much higher than that of their non-Hispanic white neighbors, especially in their younger years, this is the tip of the iceberg for the nation's broader Mexican-American community as it grows older."

Why all the differences between the two groups? Morgenstern notes that Hispanics are known to have a high rate of diabetes, which increases stroke risk, but they have similar rates of two other major risk factors—high blood pressure and high cholesterol—as non-Hispanic whites. More research is needed to look for genetic, sociocultural and other factors that might be at work.

Morgenstern started the BASIC study while he was at the University of Texas Medical School and the University of Texas School of Public Health, both in Houston. Several authors on the new papers were from those schools, and one is at the University of Pittsburgh. Other authors of the AJE study from the U-M Stroke Program are Melinda Smith, Lynda Lisabeth, Nelda Garcia and Devin Brown. Morgenstern was senior author on the Neurology paper, and Risser, Smith and Moye were co-authors.
—Kara Gavin, UMHS Public Relations

Genital pain linked to increased pain sensitivity throughout the body

Women who experience pain in the genital area often are told it's all in their head.

New research shows it may well be in the shins, arms and thumbs. Women with a condition called vulvodynia process pain differently, and these women are more sensitive to pain at other points in their body, researchers at the U-M Health System found. Results of their study appeared in the July issue of the journal Obstetrics and Gynecology.

The researchers tested 17 women with vulvodynia and 23 similar women without pain at 23 sites throughout the vulva and at the deltoid muscle, the shin and the thumbnail to assess pain tolerance. They found the women with vulvodynia had lower tolerance at all sites than the women without vulvodynia.

"Vulvodynia used to be considered a psychological problem or a sexual disorder, and was not treated as a medical problem. Now we know vulvodynia is likely a neuropathic disorder in which the nerves in the area are hypersensitive," says study author Dr. Barbara Reed, professor of family medicine at the Medical School. "We found women with vulvodynia were hypersensitive at the vulva, not only in areas that were clinically tender, but in surrounding areas as well, and at areas not thought to be tender at all—the deltoid, shins and thumb. This study shows there are neurological differences that are not psychosomatic."

Vulvodynia causes chronic and potentially severe pain at the outer genital region, or vulva. Currently, few doctors are familiar with vulvar pain disorders, and many women with intense pain are misdiagnosed for years with chronic yeast infections or psychological problems. Women with more mild pain or whose pain comes and goes often think some degree of pain in that area is normal and don't tell their doctors about it.

The study was funded from the National Institutes of Health and the U.S. Army. In addition to Reed, study authors were Dr. Hope Haefner, associate professor of obstetrics and gynecology; Dr. Daniel Clauw, professor of rheumatology; Richard Gracely, professor of rheumatology and neurology; and Dr. Jutta Giesecke and Dr. Thorsten Giesecke, research fellows.
—Nicole Fawcett, UMHS Public Relations

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