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June 8, 2006


Emergency medicine group funds research

Two Pitt doctors have received research grants from the American Society for Academic Emergency Medicine.

James Menegazzi, research professor of emergency medicine at the School of Medicine, has been named principal investigator for the society’s 2006-2008 institutional research training grant.

The grant provides support in the form of $75,000 per year for two years in order to train a research fellow who actively is developing a career in emergency medicine research.

He will use this training grant to provide a research fellow with comprehensive interdisciplinary training in basic, clinical and translational research in the field of emergency medicine.

Menegazzi also is director of research for the Center of Emergency Medicine of Western Pennsylvania and editor-in-chief of the EMS medicine journal Prehospital Emergency Care.

His research focuses on developing protocols for improved cardiopulmonary resuscitation while preserving neurological function.

William Northington, an emergency medicine services fellow at the School of Medicine, has received the society’s 2006 EMS fellowship grant.

Northington, who will begin his second year of an EMS fellowship, will receive a one-year stipend of $60,000 to support his EMS research. Northington’s research will focus on the physiological changes and dehydration of prehospital care providers and police while wearing personal protection equipment.

Through this research grant, Northington will build upon his existing research to identify ways these individuals can stay hydrated while suited up in personal protection equipment as they perform rigorous tasks.

Northington received his medical degree in 2002 from the University of North Carolina School of Medicine in Chapel Hill, followed by a residency in emergency medicine at Pitt in 2005, during which he received his paramedic degree at the Center for Emergency Medicine of Western Pennsylvania.


Cancer research presented

Pitt researchers presented results of more than 30 studies at a recent meeting of the American Society of Clinical Oncology (ASCO). Among them were:

***** New drug boosts chemo to fight lung cancer

Suresh Ramalingam of the University of Pittsburgh Cancer Institute (UPCI) received an ASCO Clinical Research Development Award for a study on a small molecule drug that appears to bolster the effects of chemotherapy for advanced non-small cell lung cancer (NSCLC) patients.

In the study, Ramalingam, assistant professor of medicine at the School of Medicine, examined the effects of three different doses of the drug vorinostat on patients with advanced NSCLC. Vorinostat is thought to stop the growth of tumor cells by altering the expression of genes necessary for cancer cell growth.

The drug was administered in 200, 300 and 400 mg doses in combination with a standard chemotherapy for NSCLC that included carboplatin and paclitaxel.

“Non-small cell lung cancer is an extremely difficult disease to treat effectively over time,” said Ramalingam. “Current approaches typically result in average survival of only eight to 11 months for patients with advanced disease. The purpose of our study was to see how safely we could add vorinostat, a novel anti-cancer agent, to standard chemotherapy. This is the first step in our efforts to determine whether the addition of this agent will improve survival for patients.”

The study included 28 patients with NSCLC, head and neck cancer, bladder cancer and mesothelioma. Eleven of these patients had a partial response to treatment and the disease was stabilized in an additional seven patients.

The 400 mg dose was well tolerated by most of the patients in the study and is the recommended dose for a subsequent study on the drug’s efficacy. Based on these initial results, a larger clinical trial at UPCI is planned, Ramalingam said.

Pitt co-investigators were Robert Parise, Merrill Egorin, Athanassios Argiris, Ronald Stoller, Lynette Beattie and Chandra Belani of the School of Medicine.

Support for the study was provided by a grant from the National Cancer Institute.

***** Breast cancer more distressing for poor black women

A study on the impact of race and income on women’s experiences with metastatic breast cancer by researchers in the nursing and medical schools found low-income African-American women more likely to report physical and social distress and uncertainty about their future.

“As more and more women are living with metastatic breast cancer, it becomes ever more important to look at how women experience the disease differently based on their unique circumstances,” said Margaret Quinn Rosenzweig, assistant professor of acute and tertiary care at the School of Nursing. “While we know that equitable treatment and symptom management are critical to breast cancer survival, we know much less about how quality of life and symptom distress vary according to women’s race and income level, particularly for women living with advanced breast cancer.”

The study looked at how women perceived barriers to treatment and to symptom management. Based on self-reporting, 57 women with metastatic breast cancer were categorized into four groups: eight low-income African-American women, eight high-income African-American women, 16 low-income white women, and 25 high-income white women. They filled out questionnaires on socio-demographics, symptom distress and quality of life, and were interviewed by the researchers to assess their experience with symptoms, self-care strategies and barriers to managing their symptoms.

The researchers found much higher symptom distress and lower quality of life reported by low-income African-American women than from the other racial and economic groups. These women also reported uncertainty regarding the goals of treatment, saying they did not know what to expect and did not feel as though the medical professionals overseeing their care explained treatment goals.

“One of the most striking findings is that just looking at race or income alone is not enough,” said Rosenzweig. “For example, low-income white women and low-income African-American women do not seem to share the same level of symptom distress. Low-income African-American women may have more vulnerability coming into advanced illness, making the experience much more difficult for them than it is for higher income African-Americans or white women.”

Rosenzweig also noted the study points to the influence that care providers can have on improving outcomes for patients by appropriately tailoring care to give women the tools they need to cope with the disease.

Co-authors of the study included Susan Sereika and Theresa Wiehagan of the School of Nursing and Adam Brufsky and Robert Arnold of the School of Medicine.

The study was funded by a grant from the National Cancer Institute to the Center for Research in Chronic Disease at the School of Nursing.

***** Rash, cancer treatment response linked

Liver cancer patients who developed a rash from treatment lived twice as long as others, a new study by UPCI researchers found.

The study included 57 patients with advanced liver, gallbladder and bile duct cancers who were not candidates for surgery. They received a new agent called lapatinib that prevents two epidermal growth factors receptor (EGFR) pathways from becoming activated in cancer cells. The EGFR pathway has been implicated in the growth and spread of many cancers.

In evaluating the toxic effects of lapatinib treatment, researchers found 20 of the patients had developed a skin rash. Those with the rash lived for an average of 10 months, compared to five months for those patients who did not develop a rash.

Although the cause is not understood, the finding may be used as a way to identify those patients who would be most likely to respond to lapatinib treatment, said Ramesh K. Ramanathan, principal investigator of the study and associate professor of hematology and oncology at the School of Medicine.

According to the study results, lapatinib was well tolerated. Primary liver cancer was stabilized in 17 patients and another two had a partial response to the treatment.

Chandra Belani of UPCI co-authored the study, which was supported by a grant from the National Cancer Institute to the California/Pittsburgh Consortium.


Gene therapy research presented

Results of a number of Pitt studies were presented at a recent meeting of the American Society of Gene Therapy. Among them were:

***** Gene therapy prevents hyperglycemia in mice

Pitt researchers have successfully prevented the onset of elevated blood sugar, or hyperglycemia, in diabetes-prone mice by inserting a gene encoding for a cytokine — a protein that stimulates or inhibits the proliferation or function of immune cells — into their insulin-producing cells.

According to lead author Khaleel Rehman Khaja, senior research associate in molecular genetics and biochemistry in the School of Medicine, results from this animal study suggest that gene therapy is a viable method for preventing the onset of type 1 diabetes in genetically at-risk people.

The findings may have significant implications for the prevention of the autoimmune disorder that affects more than 700,000 Americans. In type 1 diabetes, the body attacks the insulin-producing cells of the pancreas, causing chronic hyperglycemia and complications such as blindness, kidney failure, heart disease and nerve damage.

Others involved in this study are Zhong Wang, Xiao Xiao and Paul D. Robbins of the departments of molecular genetics and biochemistry and orthopaedic surgery at the School of Medicine.

***** Coaxing muscle stem cells to form bone

Pitt researchers have demonstrated they can increase the propensity of muscle-derived stem cells to become bone-forming cells, a discovery they believe could lead to new treatments for musculoskeletal diseases and injuries.

The technology the researchers used, called RNA interference, uses short interfering RNAs (siRNAs) — small molecules that prevent a gene from being expressed — to turn off the production of specific proteins in a cell.

In the Pitt study, researchers generated siRNAs to two mouse genes: MyoD1, a master gene that regulates the formation of muscle cells or fibers (myogenesis), and Smad6, which encodes a molecule that specifically inhibits a cell’s ability to respond to bone-forming, or osteogenic, signals.

When the researchers examined cultured cells in which myogenesis was inhibited, they found a significant increase in the cells’ bone-forming potential. However, contrary to their expectations, the researchers did not observe any bone formation when the cells were implanted in skeletal muscle. Yet when they turned off ostegenic inhibition in these same cells using Smad6 siRNA prior to implanting them in mice, 60 percent of the mice developed detectable bone within three weeks.

“By understanding the genetic mechanisms that regulate a cell’s propensity to differentiate into one type of cell line over another, we may be able to regulate their ability to generate bone for the treatment of various diseases and injuries of the musculoskeletal system, such as osteoporosis or severe fractures,” said first author Jonathan B. Pollett, a research associate in orthopaedic surgery at Children’s Hospital. Corresponding author Johnny Huard, the Henry J. Mankin Endowed Chair in Orthopaedic Surgery Research at the School of Medicine and director of the Stem Cell Research Center (SCRC) of Children’s Hospital, added that muscle and bone injuries are very frequent in sports medicine and this research may someday significantly improve the treatment of such problems.

Others contributing to this study were Jessica Tebbets, Bridget M. Deasy and Karin A. Corsi of the SCRC of Children’s Hospital.

***** Radiation damage prevented with gene therapy

School of Medicine researchers have successfully protected mice against the damaging effects that radiation can have on bone marrow using gene therapy. Based on these results, the researchers believe this approach may be able to protect first responders in the event of a radiological accident or the detonation of a crude radiological weapon, or “dirty bomb.”

Since the events of Sept. 11, there has been growing concern that terrorists may use a dirty bomb — a conventional explosive wrapped in radiological material — or attack a nuclear power facility to disperse high-dose radiation across a populated area. Experts believe a significant portion of the population would die within 30 days of exposure to a high dose of radiation from such an event, which has prompted the federal government to fund efforts to develop medical interventions against such threats.

In this study, Pitt researchers used gene therapy to deliver the compound manganese superoxide dismutase-plasmid liposome (MnSOD-PL) to the cells of female mice. Twenty-four hours later, groups of mice that received the treatment and control mice that did not were exposed to varying doses of whole body radiation. Following irradiation, the mice were weighed daily and observed for signs of irradiation-induced damage to their bone marrow.

Control mice irradiated at the higher doses lost weight and died fairly rapidly due to bone marrow damage. In contrast, mice treated with the MnSOD-PL gene therapy showed no changes in body weight, had little bone-marrow damage, and lived longer than the irradiated control mice.

Corresponding author Joel S. Greenberger, professor and chair of the Department of Radiation Oncology and co-director of the Lung Cancer Center at the University of Pittsburgh Cancer Institute (UPCI), said the results of this study have implications not only for first responders to a radiological accident or attack but also to anyone else who might be exposed.

“This treatment is probably most effective when it is administered before exposure to radiation, as would be the case for first responders entering a radioactive environment. However, we have shown that it does have post-exposure, or mitigation, properties when we’ve administered it as a supplement to bone marrow transplantation. So, it also may be effective for treating people who have already been exposed to a radioactive event,” he said.

This work was supported by the National Institute of Allergy and Infectious Diseases as part of its research program on Medical Countermeasures Against Radiological and Nuclear Threats.

Others involved in this study were Michael W. Epperly and Yunyun Niu of the Department of Radiation Oncology at UPCI.

***** Ovarian tumors in mice slowed, stopped

Researchers from Pitt’s School of Medicine have used gene therapy to abolish or significantly inhibit tumor growth in a mouse model of ovarian cancer. The findings may significantly improve the prognosis for ovarian cancer patients.

In this study, mice were inoculated with an ovarian cancer cell line. Some then were treated immediately with a genetically engineered vaccinia virus containing a gene coding cytosine deaminase, a suicide gene. Treatment of other mice was delayed for 30 or 60 days. Control mice were inoculated with ovarian cancer cells but were not given the gene therapy.

The researchers found complete inhibition of tumor growth in the mice that were treated immediately with gene therapy and significant tumor inhibition in the 30- and 60-day delayed treatment mice. In contrast, all non-gene-therapy treated mice either died or were euthanized due to overwhelming buildup of fluid in the peritoneal cavity within 94 days of tumor inoculation.

According to corresponding author David L. Bartlett, professor of surgery and chief of the Division of Surgical Oncology at the School of Medicine, gene therapy offers an attractive new approach for treating ovarian cancer. “Current treatments for ovarian cancer are fairly harsh. Given their tumor selectivity and cancer-killing potential, vaccinia vectors expressing recombinant gene products represents a potent, non-toxic alternative for treating this deadly disease,” he said.

Others involved in this research were Xiang Da (Eric) Dong, Mark E. O’Malley, Sri Chalikonda, Zongsheng Guo and Herbert J. Zeh of the Division of Surgical Oncology, School of Medicine.

***** Gene therapy speeds muscle healing

School of Medicine researchers have successfully used gene therapy to accelerate muscle regeneration in experimental animals with muscle damage, suggesting this technique may be a novel and effective approach for improving skeletal muscle healing, particularly for serious sports-related injuries.

Skeletal muscle injuries are the most common injuries encountered in sports medicine. Although such injuries can heal on their own, the formation of scar tissue may prevent a complete recovery of function. Of particular concern are top athletes who, when injured, need to recover fully as quickly as possible.

In this study, the Pitt researchers injected mice with a gene therapy vector containing myostatin propeptide — a protein that blocks the activity of the muscle-growth inhibitor myostatin — three weeks prior to experimentally damaging the mice’s skeletal muscles. Four weeks after skeletal muscle injury, the investigators observed better muscle regeneration in the gene-therapy treated mice compared to untreated control mice. There also was significantly less fibrous scar tissue in the skeletal muscle of the gene-therapy treated mice compared to the control mice.

Corresponding author Johnny Huard, the Henry J. Mankin Endowed Chair and Professor in Orthopaedic Surgery, School of Medicine, and director of the Stem Cell Research Center of Children’s Hospital, said this approach offers a significant, long-lasting method for treating serious, sports-related muscle injuries.

“Based on our previous studies, we expect that gene-therapy treated cells will continue to overproduce myostatin propeptide for at least two years. Since the remodeling phase of skeletal muscle healing is a long-term process, we believe that prolonged expression of myostatin propeptide will continue to contribute to recovery of injured skeletal muscle by inducing an increase in muscle mass and minimizing fibrosis. This could significantly reduce the amount of time an athlete needs to recover and result in a more complete recovery,” he explained.

Others involved in the study included Jinhong Zhu and Yong Li of the Growth and Development Laboratory, Children’s Hospital; and Chunping Qiao and Xiao Xiao of the Molecular Therapies Laboratory, Department of Orthopaedic Surgery, School of Medicine.


Golfers, bikers, benefit from NRL studies

Help for golfers and bicyclists to improve their performance and protect against injury can be found in the results of several research studies conducted at the University’s Neuromuscular Research Laboratory (NRL) and presented at a recent meeting of the American College of Sports Medicine.

***** Downswing crucial in golf ball speed

In a golf swing analysis of 109 male right-handed golfers, those with greater ball velocity and driving distance also had greater wrist-hinge angle and faster wrist-hinge angular velocity during the downswing compared to golfers with slower ball velocity.

Mathematical modeling shows that during the golf swing, wrist-hinge angle and wrist-hinge angular velocity prior to ball impact are important contributors to ball velocity and driving distance. But this had not been established by actual golfers prior to the study.

Swing mechanics at various reference points were assessed using a high-speed eight-camera 3D optical motion analysis system. Although the data showed no differences in wrist-hinge angle and wrist-hinge angular velocity during the top of the swing, there were significant differences during the downswing between the golfers who produced greater ball velocity and those with slower velocity.

“This result supports both the mathematical and anecdotal evidence. Furthermore, the timing of wrist-hinge angle release to achieve maximal wrist-hinge angular velocity may be critical for greater ball velocity,” said NRL researcher Timothy Sell.

***** Better golfers most consistent in ball flight

An evaluation of ball flight characteristics showed golfing proficiency is best measured by consistent ball flight characteristics (BFC), rather than traditional measures such as club velocity and total driving distance.

A golf launch monitor was used to evaluate the BFCs of 90 male golfers, each of whom performed 10 golf swings with their own drivers. For each golfer, the five swings with the greatest total driving distance were calculated.

The golfers were separated into three groups based on proficiency and low-, mid- and high-handicap.

“We saw no significant differences among the three groups for ball speed or club velocity consistency. However, significantly more consistent ball flight characteristics were demonstrated in the low-handicap group compared to the mid- and high- groups,” reported researcher Joseph Myers.

“This shows that proficient golfers are more consistent in transferring the generated power to the ball, resulting in more consistent ball flight characteristics,” he said.

*****The why behind golf swing and ball speed

Joseph Myers and his NRL research team used advanced biomechanical assessment tools to analyze the golf swing of 100 male recreational golfers. They measured upper torso rotation and velocity, pelvic rotation and velocity, x-factor (the absolute difference between upper torso and pelvic angles) and x-factor velocity during the golf swing. They also assessed ball velocity and the relationships between ball velocity and all biomechanical variables during the full golf swing. Their measurements showed that during the downswing, the x-factor contributes to increased upper torso rotation velocity and x-factor velocity, ultimately contributing to increased ball velocity.

“This study provides golf instructors with evidence to support increasing ball velocity by maximizing separation between the upper torso and pelvis,” Myers said.

***** Hip joints may suffer after knee injury

Individuals with injury to the anterior cruciate ligament (ACL) — the main stabilizing ligament of the knee joint — may be unknowingly compensating for their ACL deficiency with increased internal hip rotation, potentially furthering the progression of osteoarthritis.

An NRL study examined 10 non-injured subjects and nine ACL-deficient subjects who pedaled on a stationary cycling ergometer at a constant speed with the foot securely attached in a neutral position.

Using infrared motion analysis, researchers captured hip, knee and ankle internal/external rotation and found the ACL-deficient group had more hip internal rotation than the control group. The increased hip internal rotation was observed in both the injured limb and the uninjured limb, without any rotational changes at the knee.

“This altered hip motion may be an attempt to minimize lower leg internal rotation, which has been seen in previous studies of ACL-injured individuals. The altered hip motion in both the uninjured and injured limbs suggests a central regulation of the compensatory mechanism due to the deficiency or loss of the ACL and its mechano-receptors,” said NRL researcher John Abt.

***** Uneven pedaling can hurt

The repetitive motion of cycling requires efficient, symmetrical movement patterns to prevent excessive stresses from being transmitted to the muscles and tendons of the legs, which may be partially responsible for the development of overuse injury, according to NRL researcher John Abt.

In a biomechanical study using a 3D motion analysis system, Abt’s research team found asymmetrical movement patterns in 31 competitive cyclists. The asymmetrical cycling patterns were found specifically in knee and hip motion that is in the plane of the bike’s top tube as it splits the bike into right and left halves.

“The differences in hip and knee motion may be related to compensatory adaptations to unequal musculoskeletal characteristics or inappropriate bike fit,” said Abt. “Prolonged cycling with asymmetrical mechanics may contribute to the development of overuse injury, particularly as it relates to diagnosis of one limb.”

***** HHMI to fund biological science programs here

Pitt has been awarded a four-year, $2.1 million grant from the Howard Hughes Medical Institute (HHMI) to strengthen undergraduate research and outreach programs in biological sciences.

Pitt, along with Carnegie Mellon and Lehigh are the Pennsylvania universities named among 50 schools in the United States to receive 2006 HHMI undergraduate science education program grants.

At Pitt, the grant will fund programs in the Department of Biological Sciences that encourage undergraduate research.

Students will be able to begin research as early as the summer before their freshman year through a program called FastStart, and subsequent programs aim to keep them conducting research through graduation. Along the way, Pitt students will participate in project-based freshman biology labs and BioResearch101, a research introduction workshop for rising sophomores. During the summer after their junior year, experienced student researchers will receive training in how to mentor new students.

Pitt’s current biology outreach programs also will receive support from the grant. These initiatives include summer workshops for Pittsburgh high school science teachers in which they develop inquiry-based modules to teach their students throughout the year; “Pitt Kits” that contain supplies for teachers to implement those modules, and summer science camps for local middle and high school students. In addition, the workshops will be expanded to Allegheny College in Meadville, near Pitt’s Pymatuning Laboratory of Ecology.

Graham Hatfull, the Eberly Family Professor of Biotechnology and chair of the Department of Biological Sciences in Pitt’s School of Arts and Sciences, will administer the programs.

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