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June 14, 2007


Mutation involved in cancer growth studied

Mutations in the cell adhesion molecule known as integrin alpha 7 lead to unchecked tumor cell proliferation and a significantly higher incidence of metastasis in several cancer cell lines, report researchers at the School of Medicine in a study published in the Journal of the National Cancer Institute. These findings suggest that integrin alpha 7 represents an important new target for cancer therapy and prevention.

Integrins are a major class of cell membrane proteins that play a role in the attachment of a cell to the extracellular matrix (ECM), which holds together cells within a particular type of tissue. Integrins also help cells attach to one another and are involved in transmitting chemical signals to and from the ECM.

In this study, the researchers, led by Jianhua Luo, associate professor in the Division of Molecular and Cellular Pathology, sequenced integrin alpha 7 genes from 66 human cancer specimens and cell lines representing a number of different kinds of cancer, including cancer of the prostate, liver, brain and muscle, to discover whether the gene is mutated in specimens of various human cancers as well as whether the level of integrin alpha 7 expression is associated with clinical relapse of human cancers. They also investigated whether integrin alpha 7 has tumor suppressor activity.

They found mutations in the integrin alpha 7 gene in 16 of 28 prostate cancers, in five of 24 liver cancer samples, in five of six brain cancers, and in one of four muscle cancers.

Integrin alpha 7 mutations also were associated with a significant increase in the recurrence of cancer among patients with the mutations compared to those without them.

“Our study shows rather definitively that when we experimentally decreased the level of integrin alpha 7 protein or the protein was naturally mutated in cells, those cells lost their inhibitory signals for both cell migration and proliferation,” Liu said. “It suggests that if we can somehow restore normal integrin alpha 7 levels in tumor cells in vivo, we may be able to reduce the risk of them spreading to other sites.”

This work was supported by the National Cancer Institute, Pitt’s Department of Urology and the John Rangos Foundation for Enhancement of Research in Pathology.

Other researchers involved were George Michalopoulos, Baoguo Ren, Yan Yu and Chuanyue Wu of pathology, George Tseng of biostatistics in the Graduate School of Pubic Health, and Ka Chen, Uma Rao and Joel Nelson of urology.


Study looks at CBT therapy

In a community-based effort to promote effective discipline and foster positive parent-child interactions, Pitt is offering free training to counselors at agencies in Allegheny and Butler counties in an evidence-based intervention. This effort, funded by the National Institute of Mental Health, aims to teach focused cognitive-behavioral therapy (CBT) to families who are concerned about how they use physical discipline or those who have a history of physical abuse.

Developed by a team at the School of Medicine led by principal investigator David Kolko, professor of psychiatry, psychology and pediatrics, focused CBT is one of only a few scientifically proven interventions for families who have problems with physical discipline and/or physical abuse.

The focused CBT being used integrates several complementary approaches to help families change the way they think, feel and act. The skills are designed to promote self-control and help families solve problems safely and effectively.

This is the first rigorous study to determine whether the therapy is feasible and effective when used in community settings.

Participating agencies include Auberle, Every Child Inc., Family Links, Family Resources, Western Psychiatric Institute and Clinic, Rankin Christian Center, Northshore Community Alliance and Family Pathways.

Co-investigators are Barbara L. Baumann and Amy D. Herschell of psychiatry and Stephen Wisniewski of epidemiology in the Graduate School of Public Health.


Pitt leads brain injury study

P. David Adelson, A. Leland Albright Professor of Neurosurgery at the School of Medicine and director of the Pediatric Neurotrauma Center at Children’s Hospital, will lead researchers at 12 U.S. sites in an $11.5 million study of the effectiveness of induced hypothermia as a therapy for brain swelling in children who have suffered traumatic brain injuries.

The study is being funded by the National Institute of Neurological Disorders and Stroke.

A previous trial led by Adelson found that moderate hypothermia therapy is safe and potentially may improve outcomes. Results were published in the journal Neurosurgery in April 2005.

Adelson said, “The belief is that cooling impacts the cascade of events that leads to brain swelling. Reducing brain swelling potentially could prevent further injury.”

Patients will be cooled to approximately 89-90 degrees Fahrenheit using special cooling blankets and/or cooled saline injections for 48 hours, then followed by researchers for one year to track outcomes.


Cancer research presented

Researchers from the School of Medicine presented findings at the American Society of Clinical Oncology annual meeting this month. Highlights of their research include:

* Protein’s role in melanoma return studied

Higher levels of a protein called S-100 in patients with melanoma may correlate with a higher risk of having the disease return, say researchers at the University of Pittsburgh Cancer Institute.

The study evaluated serum samples from 103 patients who were treated with high-dose interferon, a standard immunotherapy treatment for melanoma, an average of eight years prior. The disease recurred in 64 of the patients within an average of 30 months. When the researchers examined levels of S-100 in the serum samples, they found that the higher the level of the protein, the greater likelihood the patient’s disease had returned.

* Herceptin doesn’t increase heart failure in breast cancer patients

Risk of congestive heart failure in women treated with trastuzumab (Herceptin) and combination chemotherapy for early-stage breast cancer did not increase over time, according to a five-year follow-up of National Surgical Adjuvant Breast and Bowel Project trial B-31. Based on the findings, the research team developed a prediction model to help oncologists assess the risk of heart failure in individual breast cancer patients prior to treatment with Herceptin and chemotherapy.

* Two-step approach may help lymphoma patients

Patients treated for follicular lymphoma, a slow-growing type of non-Hodgkin’s lymphoma, may benefit from chemotherapy followed by radioimmunotherapy, (treatment with a radioactive substance that is linked to an antibody that will attach to a tumor when injected into the body), according to a UPMC study.

More than 90 percent of patients responded completely to the treatment and, since only a short course of chemotherapy was used, side effects were limited. The researchers also found that PET scanning was useful in determining those patients who were at highest risk for relapse.


Additional Rx helps elderly with depression

Adding a medication to a standard treatment regimen for major depressive disorder in the elderly improves chances of recovery in those who do not respond adequately to the first-course therapy or who relapse from it, finds a School of Medicine study published in the June issue of the American Journal of Psychiatry. Up to 84 percent of the elderly who experience depression either fail to respond to first-course treatment or relapse during the first six to 12 weeks of treatment.

The study found that adding a second drug (sustained-release bupropion, nortriptyline or lithium, selected based on each patient’s medical status and history) to the treatment of depressed participants over the age of 70 who either did not respond to initial treatment with the antidepressant paroxetine and interpersonal psychotherapy, or to those who responded to the initial treatment but quickly relapsed, caused the likelihood of recovery to rise from 40 percent to 60 percent.

Half of the patients who did not respond to the initial treatment responded to the augmentation therapy. It took a median 28 weeks for the participants to achieve recovery. Of the patients who relapsed after the initial therapy, 67 percent recovered after augmentation over a median recovery time of 24 weeks. Of the patients who responded to the first-course therapy of paroxetine and psychotherapy, 87 percent achieved recovery.

Mary Amanda Dew, professor of psychiatry, psychology and epidemiology, was lead author of the study. Pitt co-authors were Ellen M. Whyte, Eric J. Lenze, Patricia R. Houck and Benoit H. Mulsant of psychiatry, Bruce G. Pollock of pharmaceutical sciences, Jacqueline A. Stack, director of the Late-Life Mood Disorder Evaluation and Research Center, Charles F. Reynolds III of psychiatry, neurology and neuroscience and Salem Bensasi, a database manager at WPIC.

The National Institute of Mental Health funded the study.


Gene patterns can ID rapid IPF progression

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease typically characterized by the slow but progressive onset of shortness of breath or cough. Most patients live about five years after diagnosis. However, according to a study published in the online journal PLoS ONE, a subset of patients with a specific genetic profile has a much more rapid progression to complete pulmonary failure and death without a lung transplant.

Based on observations that some IPF patients display a more rapidly progressing disease course, researchers at the Simmons Center for Interstitial Lung Disease at Pitt’s School of Medicine, collaborating with pulmonary scientists in Mexico and California, used DNA microarray analysis to measure the gene expression patterns of 26 rapid progressors and 88 slow progressors. They identified 437 differentially expressed genes between the groups and found that the lungs of rapid progressors (predominantly males who smoked overexpressed genes involved in the development of tissues and organs (morphogenesis), oxidative stress, cell migration and proliferation, and genes from fibroblasts and smooth muscle cells.

According to Naftali Kaminski, director of the Simmons Center and director of the Lung Translational Genomics Center in the School of Medicine, these findings offer strong evidence that rapid progressors represent a distinct clinical phenotype.

This study was supported by the National Institutes of Health, the Simmons Family Foundation and the Universidad Nacional Autónoma de México.

Other Pitt researchers involved in the study were Thomas Richards and James Dauber, both of the Simmons Center and the medical school.


Gene therapy researchers report findings

Pitt researchers were among the presenters at the annual meeting of the American Society of Gene Therapy in Seattle.


Protecting cells from radiation damage

A School of Medicine research team, collaborating with scientists from Stanford University, have developed a new, smaller gene therapy vector that may spare healthy tissue the long-term consequences of therapeutic irradiation.

Combined with intensive chemotherapy, high dose whole-body irradiation often is given to patients with blood and lymphatic cancers to wipe out their bone marrow cells prior to subsequent transplantation of hematopoietic stem cells, bone marrow stem cells or peripheral blood progenitor stem cells. However, there is increasing concern that such high doses of radiation may have long-term negative effects on healthy tissues and organs, such as the kidney, liver and thyroid gland.

Based on studies showing that intravenous gene therapy delivery of the enzyme manganese superoxide dismutase (MnSOD) could protect mice from whole body irradiation, and in preparation for a potential clinical trial of systemic MnSOD in humans, the researchers, led by Joel Greenberger, chair of the medical school’s Department of Radiation Oncology, delivered the human MnSOD enzyme into mouse hematopoietic progenitor cells using a newly constructed gene therapy vector called a “minicircle” plasmid.

The MnSOD transfected cells were significantly more resistant to ionizing radiation than non-transfected cells. According to Greenberger, whose group is conducting a phase I/II clinical trial in lung cancer patients consisting of twice-weekly swallowed MnSOD for protection of the esophagus from chemoradiotherapy damage, these results suggest that minicircle DNA containing the human MnSOD transgene confers undiminished radioprotection to cells.

“Because we now can deliver MnSOD in this very small vector, we will be able to get this radioprotective enzyme more efficiently into all of the cells of the body and give patients receiving total body radiation for systemic cancers better long-term outcomes. This also has implications for the prophylactic protection of those who may be the first responders to a nuclear accident or a terrorist attack, such as a “dirty bomb,” Greenberger explained.


Causes of genetic instability sought

Genomic instability — the rearrangement of chromosomes or an abnormal number of chromosomes — is a hallmark of many human cancers. Although the source of genomic instability has been established for many inherited human cancers, the processes and genes involved in cancers that that are not inherited remain largely unknown.

Now, researchers at the School of Medicine say they have the ability to study the potential cause of genomic instability in sporadic cancers using a recombinant adeno-associated virus (rAAV), the same virus that many researchers around the world use for gene therapy experiments.

Recent research has demonstrated that rAAV can insert itself only into host chromosomes at sites that are prone to DNA breaks.

The research team, led by Hiroyuki Nakai, assistant professor of molecular genetics and biochemistry, recently established a novel method to isolate rAAV integration sites in non-dividing cells on a large scale. They have used this method to identify approximately 1,000 integration sites in mouse liver, skeletal muscle and heart. Furthermore, of 945 rAAV integration sites mapped to the mouse genome, Nakai and his collaborators found that up to 30 percent of the integration events occurred in DNA palindromes (whose base pairs read the same backwards and forwards across the double strands). A series of bioinformatic and statistical analyses revealed that these breakage-prone palindromes can be found throughout the genome, but only a subset of a particular size are susceptible. According to Nakai, the discovery that rAAV can selectively identify breakage-prone palindromes allows researchers to study these naturally occurring DNA sequences on a whole genome scale in various tissues in living animals and human cells.

“Our findings … can contribute significantly to our understanding of the possible contributions to cancer and aging,” he explained.

Katsuya Inagaki and Congrong Ma of the Department of Molecular Genetics and Biochemistry also were involved in the research.


Gene therapy treatment can ease pain

School of Medicine researchers report they have used gene therapy to block the pain response in an animal model of neuropathic pain.

Neuropathic pain is the result of damage to nerve fibers caused by injuries or diseases, such as diabetes and cancer. These damaged nerve fibers continue to send signals to pain centers in the brain even after the surrounding tissue has healed. Unfortunately, neuropathic pain often responds poorly to standard pain treatments and occasionally may get worse instead of better. For some people, it leads to serious, long-term disability and dependence on pain medications.

The team, led by Joseph Glorioso, chair of the Department of molecular Genetics and Biochemistry in the School of Medicine, used a genetically engineered herpes simplex virus (HSV) to deliver the gene for part of the human glycine receptor (GlyR), a receptor found primarily on the surface of nerve cells in the spinal cord and the lower brain but not in the nerves of the limbs, to the paws of rats. A group of control rats received only the HSV vector without the inserted gene. The researchers then injected the same paws of each rat with formalin, an irritant known to simulate the symptoms of a peripheral neuropathic pain. The rats then were given an injection of glycine to activate the GlyR receptor.

Both groups showed a typical pain response to formalin. However, the application of glycine eliminated the pain response in GlyR-HSV infected animals, while it had no effect on the control group.

According to Glorioso, these findings suggest that HSV-directed expression of GlyR in peripheral neurons and subsequent selective activation by glycine has the potential to be used therapeutically not only for neuropathic pain management but a variety of pain syndromes.

Others involved in the study included Michael Cascio, James Goss, David Krisky and Rahul Scrinivasin, all of molecular genetics and biochemistry.


Gene therapy for erectile dysfunction

Rats with erectile dysfunction, or ED, that were injected with a gene therapy vector containing either of two nerve growth factors were able to regain normal function after four weeks, according to a study conducted by School of Medicine researchers.

ED is the repeated inability to achieve or maintain an erection necessary for sexual intercourse. Estimates of the incidence of ED vary but range from 15 million to 30 million affected men in the United States. ED is frequently associated with damage to the cavernous nerve that results from surgery for prostate cancer.

In this study, led by Joseph Glorioso and Joel Nelson, chair of urology, researchers inserted either the gene for the glial cell line derived neurotrophic factor (GDNF) or the GDNF family ligand (neurturin) into a genetically engineered herpes simplex virus (HSV). They then injected either of the recombinant viruses into the damaged cavernous nerve of rats.

GDNF is an important nerve growth promoter and has been shown in other studies to contribute to survival and regeneration of penile nerves. Neurturin also is a nerve growth factor closely related to GDNF. Control mice received only the virus without the GDNF or neurturin genes inserted.

After four weeks, the rats treated with the genes showed significant recovery of intracavernous pressure (ICP) and systemic arterial pressure (AP) compared with the control group of untreated animals. Fluorescent protein studies also showed that the delivered genes had been incorporated effectively into the target nerve cells.

“This represents the first-ever demonstration of a long-term treatment for ED that does not rely on the chronic administration of drugs that can have potentially harmful side effects,” Glorioso said.

Other researchers involved in the study included William F. Goins, Shaohua Huang, James B. Wechuck and Darren P. Wolfe of molecular genetics and biochemistry, and Ryuichi Kato, Naoki Yoshimura, Christian Coyle, Michael Chancellor and Fernando de Miguel of urology.


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