University Times

Gene affects radiation damage

University of Pittsburgh Cancer Institute (UPCI) researchers have identified a gene that may play a role in promoting radiation-induced intestinal damage. The research, published in the June issue of the journal Cell Stem Cell, could lead to new strategies for protecting normal tissues from radiation during cancer treatment.

Although radiation is one of the most effective treatments for cancer, damage to cells lining the gastrointestinal tract is a major limiting factor for patients undergoing pelvic or abdominal radiotherapy. The specific mechanisms that underlie radiation-induced gastrointestinal toxicity, known as gastrointestinal (GI) syndrome, are not well understood. Previous studies suggested that damage to intestinal stem cells or blood vessel cells, which are called endothelial cells, may be involved.

Jian Yu, assistant professor of pathology, and Lin Zhang, associate professor of pharmacology and chemical biology, both of UPCI and the School of Medicine, led the team that found the expression of the gene known as p53 upregulated modulator of apoptosis (PUMA) to play a key role in the process of radiation-induced cell death in intestinal stem cells. The team’s previous research found PUMA plays an essential role in apoptosis (programmed cell death).

In the current study, Yu and her colleagues found that deficiency of PUMA in mice impaired cell death in intestinal stem and progenitor cells, enhanced regeneration of intestinal tissue and prolonged survival following lethal doses of radiation.

“We are very excited to learn that deficiency in a single gene significantly protects against GI syndrome,” said Yu. “Selectively curbing radiosensitivity in the normal tissues transiently by PUMA inhibitors might be particularly beneficial in cancer therapy. Such inhibitors might also mitigate radiation injury in an event of accidental or intentional exposure.”

The study was funded by the National Institutes of Health and private foundations. Co-authors included Wei Qiu, Michael Epperly, Joel S. Greenberger and Hongato Liu of UPCI.

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SIS profs get Army funding

School of Information Sciences faculty members Prashant Krishnamurthy and David Tipper are among a dozen collaborators at seven universities on a research project funded by the Army Research Office’s Multi-University Research Initiative.

The five-year, $6.25 million research collaboration centers on the construction of robust and secure mobile ad hoc networks.

“ARSENAL: A cross layer ARchitecture for SEcure resilieNt tacticAL mobile ad hoc networks” is a joint effort among professors at Pitt, Penn State, the University of California’s Davis, Santa Cruz and Riverside campuses, Brigham Young University and the University of Utah.

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Weight gain may aid type 1 diabetics

Gaining body fat may be a good thing, at least for people with type 1 diabetes, say researchers from Pitt’s Graduate School of Public Health (GSPH). Their study, presented last week at a meeting of the American Diabetes Association, followed 655 patients with type 1 diabetes for 20 years and found that patients who gained weight over time were less likely to die.

The findings come from the long-term Pittsburgh Epidemiology of Diabetes Complications Study, which began in 1986. Participants in the study, an average age of 28 when entering the study and 44 at its completion, were diagnosed with type 1 diabetes between 1950 and 1980.

Researchers measured patients’ body mass index (BMI) and waist circumference and assessed BMI every two years during the study period. Over the course of the study, 147 deaths occurred.

Results showed that patients whose BMI increased the most during the study (2-11 points or about 10-55 pounds) were one-third less likely to die than those who had smaller increases in BMI, indicating that weight gain may protect people with type 1 diabetes from premature death.

“Although weight gain in adulthood is typically associated with increased mortality, this may not be the case for those with type 1 diabetes,” said GSPH epidemiology professor Trevor Orchard. “Gaining a reasonable amount of weight may be a sign patients are getting enough insulin and appropriately controlling their disease, which may partly explain why those who gained weight over time had lower mortality rates,” said Orchard, who also is professor of medicine and pediatrics in the School of Medicine.

Orchard and colleagues also looked at BMI ranges and found no difference in mortality between those with a BMI in the overweight range (BMI 25-30) and the normal range (BMI 20-25), but noted that having a BMI in the underweight (BMI less than 20) or obese range (BMI 30 and greater) was a strong predictor of mortality.

When researchers controlled for waist circumference, a commonly cited reason for general fat mortality, patients with a BMI in the underweight range were at greatest risk for death, while those with a BMI in the overweight or obese ranges had a decreased risk of mortality compared to patients with a normal BMI.

“These results are not a firm recommendation to people with type 1 diabetes to put on weight, but it does raise the possibility that weight recommendations in type 1 diabetes may be somewhat different than those for the general population, and emphasizes the complex relationship between body fat and mortality in diabetes,” said lead author Baqiyyah Conway of epidemiology.

Other Pitt authors of the study were Rachel G. Miller, Tina Costacou, Rhobert Evans and Sheryl Kelsey of epidemiology and Linda Fried of medicine.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.

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Diabetes research published

Diabetes researchers at the John G. Rangos Sr. Research Center at Children’s Hospital have identified a potential target for the development of new therapies to treat hypertriglyceridemia, a lipid disorder commonly seen in people who are obese and diabetic. Results of their study are published in the June issue of the Journal of Clinical Investigation.

Scientists in the Division of Immunogenetics at Children’s Hospital studied the role of a protein known as Forkhead Box O1 (FoxO1) that mediates the metabolism of glucose and cholesterol. The researchers were able to curb the secretion of triglycerides in obese diabetic animals by inhibiting the production of FoxO1 in the liver. Elevated triglyceride levels have been identified as a risk factor for heart disease.

Their research suggests that FoxO1 is vital to the regulation of a protein known as microsomal triglyceride transfer protein (MTP). MTP facilitates the production of very low-density lipoproteins (VLDL), which are produced in extreme excess in people with hypertriglyceridemia. The study found that FoxO1 mediates insulin action on the production of MTP in the liver. Augmented production of MTP, caused by the inability of insulin to regulate the activity of FoxO1, led to the overproduction of VLDL and hypertriglyceridemia in mice. Mice that were made to be deficient in FoxO1 in the liver experienced reduced MTP and VLDL production.

Having determined FoxO1’s role in the liver, Children’s researchers now are studying its function in other tissues and organs to determine what impact such therapies might have on children and adults who are obese and/or have type 2 diabetes, which put a person at risk for heart disease.

Henry Dong, the study’s senior author who also is an assistant professor of pediatrics in the School of Medicine, said: “Our latest findings suggest that we may eventually be able to develop drug therapies that inhibit FoxO1, which would thereby inhibit the production of proteins that lead to elevated triglyceride levels in people who are obese and/or who suffer from type 2 diabetes.”

Adama Kamagate of the Rangos Research Center was the study’s lead author.

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Differential signaling patent awarded

The University has been awarded a patent, No. 7358869, for “Power efficient, high bandwidth communication using multisignal-differential channels.” Inventors were Donald M. Chiarulli of computer science and Steven P. Levitan of electrical and computer engineering.

The innovation is a low-power, area- and pin-efficient signaling alternative to traditional differential signaling methodologies.

The multi-bit differential signaling has comparable electrical characteristics to conventional low-voltage differential signaling (LVDS) but uses less power and fewer input/output pads than equivalent LVDS links.

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Monkey think, robo-arm do

Researchers from the School of Medicine report in the journal Nature that a monkey has been trained to feed itself by controlling a human-like robotic arm with signals from its brain.

Monkeys in the lab of neurobiology professor Andrew Schwartz are able to move a robotic arm to feed themselves marshmallows and fruit while their own arms are restrained. Probes inserted in the monkey’s motor cortex, a brain region where voluntary movement originates, allow neuronal activity to be evaluated by software and sent to the arm, which carries out the actions the monkey intended to perform with its own limb.

“The monkey learns by first observing the movement, which activates his brain cells as if he were doing it. It’s a lot like sports training, where trainers have athletes first imagine that they are performing the movements they desire,” Schwartz, the report’s senior author, said.

“Our immediate goal is to make a prosthetic device for people with total paralysis. The more we understand about the brain, the better we’ll be able to treat a wide range of brain disorders, everything from Parkinson’s disease and paralysis to, eventually, Alzheimer’s disease and perhaps even mental illness.”

Other Pitt authors were bioengineering graduate students Meel Velliste, Sagi Perel, M. Chance Spalding and Andrew S. Whitford.

The study was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.

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Cancer research presented

Researchers from the University of Pittsburgh Cancer Institute were among the presenters at a meeting of the American Society of Clinical Oncology.

*** Pre-surgery combo found safe

Treating pancreatic cancer with a combination of chemotherapy, biotherapy and radiotherapy prior to surgery is safe and may be beneficial for patients, according to a study by physicians from UPMC’s Pancreatic Cancer Center who examined the safety of combining gemcitabine with bevacizumab and radiotherapy in patients with operable pancreatic cancer.

In the study, 14 patients with potentially operable tumors completed the treatment regimen. Following treatment, 10 of the patients were considered eligible for surgery. The incidence of serious adverse events following surgery was not increased in these patients, and several demonstrated significant shrinkage of their tumors.

“The results from the first phase of this two-phase trial are encouraging,” said A. James Moser, lead author of the study, co-director of the Pancreatic Cancer Center and assistant professor of surgery at the School of Medicine. “Patients who receive surgery for pancreatic cancer tend to have better outcomes than those who don’t, and this treatment allows us to reduce the tumor size prior to surgery.”

Patients are being enrolled for the study’s second stage, which will further evaluate the effectiveness of the treatment.

Co-authors of the study included H.J. Zeh, R.K. Ramanathan, A.M. Krasinskas, M.E. Tublin, R.P. Smith, F. Stover, K.K. Lee, S.J. Hughes and D.L. Bartlett, all of UPMC Cancer Centers.

The study is sponsored by Genentech.

*** Biotherapy combo found promising

Researchers in the melanoma and skin cancer program at UPCI combined two biotherapies — treatments that stimulate the immune system to fight cancer — and found the results promising in terms of anti-tumor effects and tolerable in terms of toxicity in patients with inoperable melanoma.

In a phase 2 clinical trial, 16 patients with stage 4 melanoma who had received and not benefited from at least one round of previous therapy were given the combination of high-dose interferon alfa-2b (a standard treatment for metastatic skin cancer) and tremelimumab (an antibody thought to instigate the body’s immune system to attack tumors). The overall response rate was 19 percent, and the study has since moved into the second stage, where it will enroll 21 additional patients.

“With each new study, we learn something important about melanoma,” said John M. Kirkwood, leader of the program and professor and vice chair for clinical research in the School of Medicine’s Department of Medicine.

“With this study, we learned that adding tremelimumab to traditional treatment is not only safe, but an effective way to induce an anti-tumor response, which is very exciting.”

Other Pitt researchers participating were lead author Ahmad Tarhini, S.S. Moschos, J.J. Schelsselman, J. Shipe-Spotloe and M. Denmark.

*** New combo may be better for head, neck cancers

Patients treated for locally advanced head and neck cancer may respond better with the addition of cetuximab to chemotherapy, according to a UPCI phase II study.

In the study, 39 patients with stages 3 or 4 head and neck cancer were treated initially with a combination of docetaxel, cisplatin and cetuximab, after which they received radiation therapy and additional cisplatin and cetuximab. Cetuximab (also known as Erbitux) often is prescribed for metastatic colorectal cancer and is used in conjunction with radiation therapy to treat squamous cell carcinomas of the head and neck. This is the first time it has been used in combination with docetaxel and cisplatin as induction therapy.

Ethan Argiris, lead investigator and medical director of the aerodigestive cancers program and co-leader of the head and neck cancer program at UPCI, said: “We found that adding cetuximab to standard chemotherapy helped head and neck cancer patients respond better to treatment. Out of 37 patients, 32 responded to induction treatment for an 86 percent response rate, and all patients had their tumors reduced, either partially or completely, after radiation was completed.”

Further evaluation of this treatment shows that the complete disappearance of the primary tumor occurred in about 80 percent of patients, and after two years the same percentage of patients remained cancer-free. “Given that the majority of our patients had stage 4 disease, our efficacy results are thus far very encouraging,” said Argiris. In addition, the UPCI investigators noted that treatment-related toxicities were expected and manageable.

Argiris and his colleagues are planning more clinical studies using this regimen.

“While longer follow-up will be needed to assess long-term efficacy and side effects, the addition of cetuximab to chemotherapy and radiotherapy is very promising and could become the standard of care in the next few years,” said Argiris. “The results from this trial, and the possibilities we are witnessing with novel agents, are allowing us to be optimistic about the future of patients with head and neck cancers,” he said.

Pitt co-investigators included M. Gibson, D.E. Heron, R. Smith, R.L. Ferris, S.Y. Lai, S. Kim, B.F. Branstetter, J.T. Johnson and J.R. Grandis.

The study was supported in part by Bristol-Meyers Squibb, cetuximab’s manufacturer.

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Mini heart pump tested

A miniature heart pump is under evaluation at UPMC to determine whether it could eliminate the need for emergency open-heart surgery in patients undergoing high-risk coronary catheter procedures. The research study will determine its safety and efficacy in high-risk patients.

UPMC is among the U.S. heart centers participating in the PROTECT II pivotal trial with Abiomed’s Impella 2.5 System — the world’s smallest heart pump, which is only slightly larger in diameter than a drinking straw.

The device, which has not yet been approved by the U.S. Food and Drug Administration, is inserted in a cardiac catheterization lab, much the same as a balloon angioplasty and stent. Once the heart pump is secured, the regular balloon angioplasty and/or stent procedure is completed.

This pump is being tested to determine if the patient’s heart can rest and recover by reducing the heart’s workload and oxygen intake and to improve heart function even after the procedure. Patients will be supported on the device during the cardiac catheterization procedure. However, if the cardiologist decides that the patient’s heart should be supported for a longer time, the Impella can be left in place for up to five days.

Researchers hope to enroll 150 patients overall during the two-year multi-center clinical feasibility trial, which is being funded by Abiomed.

“This is an important study because it will allow us to evaluate how we can improve treatment of patients undergoing high-risk percutaneous coronary intervention procedures, especially with a growing aging population,” said cardiology professor Suresh Mulukutla, principal investigator of the Impella trial.

“Furthermore, this clinical trial highlights the growing trend of non-surgical treatments for heart patients.”

Co-investigator Michael P. Siegenthaler of the Division of Cardiac Surgery and the UPMC Heart, Lung and Esophageal Surgery Institute, said, “One of the potential main advantages of the Impella is that it may eliminate the need for major surgery with an open chest incision and placement of the patient on heart/lung bypass.

“This miniature pump is placed percutaneously with a small incision at the groin and inserted much the same way as a balloon tip or cardiac stent, which means less recovery time, fewer complications and shorter hospital length-of-stay.”

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Prof wins biomedical research award

Lee Antoinette Darville, a professor in the School of Medicine’s Department of Pediatrics, was among a dozen researchers recently named as recipients of the 2007 Hartwell Individual Biomedical Research Awards.

Given by the Tennessee-based Hartwell Foundation, the awards provide support of $100,000 a year for three years for biomedical research with potential benefit to children.

Darville’s research focuses on the development of a vaccine to protect against chlamydial infection-induced infertility and blindness. Her winning proposal was titled, “Development of Live Attenuated Vaccines Against Chlamydial Eye and Genital Tract Disease.”

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