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October 24, 2002


Investigators discover proteins linked to colon cancer

Findings published in this month's issue of Clinical Cancer Research may bring researchers one step closer to the development of tumor markers to detect colon cancer before it has had a chance to spread and when it is easier to cure, say researchers from the University of Pittsburgh Cancer Institute (UPCI).

These tumor markers — elevated levels of proteins or other substances in the blood, urine or tissue that indicate the presence of cancer — also could help identify which patients with colon cancer are more likely to develop recurrent disease.

Robert Getzenberg, senior author and associate professor of urology, pathology and pharmacology at Pitt and co-director of UPCI's Prostate and Urologic Cancer Program, and his colleagues analyzed cancerous tissue resulting from colon cancer that had spread to the liver (the most common site for colon cancer to recur) and found three proteins present in the diseased liver tissue that were not present in normal liver tissue.

The findings add to previous findings published earlier this year in the journal Cancer Research in which the same researchers identified four different proteins present in colon cancer tumor samples that were not found in normal colon tissue.

Getzenberg said, "Early diagnosis of recurrent colon cancer is critical to effective treatment of the disease, however, colon cancer metastases are very difficult to pick up early. Thirty-five to 40 percent of all patients with colon cancer have recurrent disease and the majority of these patients cannot be cured and will eventually die."

The researchers analyzed a subset of proteins in the cell nucleus called nuclear matrix proteins, or NMPs, to examine the cellular changes in tissue that occur as colon cancer grows.

"NMPs appear to represent the earliest changes that occur in cells," explained Getzenberg. "In the first study, we looked at the specific NMPs present in cancerous colon tissue and in the second, we examined the NMPs present in liver metastases that had resulted from colon cancer. We found that there are several proteins present in the diseased tissue that are not present in the normal tissue, indicating that these proteins are specifically linked to the development of colon cancer."

"These are promising results since microscopic changes indicative of liver metastasis are not currently detectable by conventional imaging studies," said Robert Schoen, study co-author and associate professor of medicine, Division of Gastroenterology, Hepatology and Nutrition, and director of UPCI's Colorectal Cancer Prevention Program.

"Carcinoembryonic antigen, or CEA, a tumor-associated glycoprotein, is the most commonly used blood test to survey patients treated for colorectal cancer for possible recurrence, but it is only somewhat useful since only half of colorectal cancers shed CEA levels sufficient for detection and often, by the time a rising CEA is detected, the tumor is too far advanced for effective re-treatment."

In subsequent studies, the researchers plan to develop antibodies against the identified proteins to detect their presence in tissue, serum and stool samples from patients.

In the United States, colorectal cancer accounts for 11 percent of all cancers with 147,300 new cases and 56,000 deaths estimated in 2002. For patients with advanced disease, five-year survival rates are 10-20 percent. However, when colon cancer is diagnosed at an early, localized stage, the five-year survival rate is 90 percent.

The study was supported by a grant from the National Institutes of Health and in part by the A.v. Humboldt Foundation, Germany.


Researchers find marker for clotting in patients who suffer cardiac arrest outside hospital

When a patient's heart stops and goes into cardiac arrest, the patient's blood begins to clot, a process that begins as early as six minutes after cardiac arrest and may hamper resuscitation efforts.

Even after resuscitation, it is possible that blood clots that form within blood vessels can lead to organ failure and ultimately death.

Researchers in the Pitt medical school's Department of Emergency Medicine tried to determine the extent to which increased blood clotting occurs in patients who suffer cardiac arrest outside the hospital. Using blood samples collected from 28 patients, the researchers found that all but one patient showed evidence of clot formation within the veins and that clotting increased the longer the patient was in cardiac arrest.

Their results were reported recently at the American College of Emergency Physicians Scientific Assembly 2002, Research Forum.

"These findings will add to our understanding of the changes that occur during cardiac arrest outside the hospital so that we can design strategies to improve survival," said Clifton Callaway, a Pitt assistant professor of emergency medicine.

Researchers collaborated with municipal paramedics who were called to the scene of cardiac arrest. Blood samples were taken from those 28 patients who were between 30 and 80 years of age (with a mean age of 55). Seventy-five percent of the patients were male.

"It is worth noting that the one patient with no sign of clotting went into cardiac arrest in the presence of paramedics and was immediately resuscitated with an external defibrillator. The patient responded quickly with no impaired mental or neurological complications," explained Callaway.

The researchers also determined from the blood tests that the longer a patient was in cardiac arrest, the more the patient's blood clotted.

Most deaths from sudden cardiac arrest occur outside the hospital. Resuscitation efforts are often unsuccessful when started more than five minutes from collapse, and less than 10 percent of patients survive sudden cardiac arrest.

In addition to Callaway, other authors were David Newman, an emergency medical services research fellow, and David Hostler, visiting research instructor, both with Pitt's emergency medicine department.

This study was funded in part by the Pittsburgh Emergency Medicine Foundation.


Pitt researcher gets grant for AIDS vaccine development

Ronald Montelaro, professor of molecular genetics and biochemistry in Pitt's School of Medicine, has received $90,000 from the American Foundation for AIDS Research (amfAR) to conduct research that will contribute to the development of a more effective AIDS vaccine.

Montelaro will examine whether chains of sugar molecules within the envelope, or surface, of the AIDS virus prevent immune cells from breaking into the cell, effecting an immune response.

"Most of the AIDS vaccines that have been created thus far have failed to stimulate an ideal immune response," said Montelaro. "Our graduate student, Surojit Sarkar, theorized that these vaccines may be rendered ineffective by the dense shield of sugar chains that surround the virus."

Getting around the chain of sugar molecules will pave the way for Montelaro and his team of researchers to begin developing a more effective AIDS vaccine.

AmfAR is a nonprofit organization dedicated to the support of AIDS research, AIDS prevention, treatment education and the advocacy of sound AIDS-related public policy.

Since 1985, amfAR has invested nearly $190 million in support of its programs and awarded grants to more than 1,900 research teams worldwide.


Pitt focuses on careers in women's health research

The School of Medicine and Magee-Womens Research Institute are among a dozen institutions nationwide to share in an innovative effort to foster the expansion of women's health research and training through the National Institutes of Health's Building Interdisciplinary Research Careers in Women's Health (BIRCWH) program.

The Pittsburgh team is receiving a total of $2.2 million in government support over five years.

"This grant will help to formalize relationships among women's health investigators throughout the University of Pittsburgh, who are coming together for this opportunity to train future researchers in women's health," said James M. Roberts, director of the Magee-Womens Research Institute and professor and vice chair of research in Pitt's Department of Obstetrics, Gynecology and Reproductive Sciences.

Roberts is principal investigator. He will work with Melissa McNeil, who is women's health program director for the University of Pittsburgh Physicians and a Pitt professor of medicine. McNeil will be program director for the grant project.

The money will be used to provide career development for junior faculty planning careers in fundamental, clinical, epidemiological or health services avenues of women's health research.

The program touches many areas of women's health throughout Pitt and UPMC Health System by incorporating four themes:

* "Gender Specific Developmental Medicine: From Gametogenesis to Birth" recognizes that gender specific differences in health predate even conception, beginning with the female gamete, or egg. The formation of these cells is strikingly different from that of males, beginning in the womb and ending at menopause.

Gerald Schatten, director of the Pittsburgh Development Center, leads this team of mentors to spearhead research that includes work on assisted reproductive technologies, the cell biology of fertilization and intense study of stem cells.

* "Research in Female Reproductive Health: Prevention of Adverse Reproductive Outcomes" focuses on issues related to female reproductive health including pre-term birth, sexually transmitted diseases, pelvic inflammatory disease, abnormal pregnancy and pelvic floor dysfunction.

Richard Sweet, the Lawrence Milton McCall Professor and chairperson of Pitt's obstetrics, gynecology and reproductive sciences department, is team leader.

* "Women's Behavioral Health" recognizes that mind and body are inextricably linked. Areas of research, led by Harold Pincus, professor and executive vice chair of the Pitt medical school's psychiatry department, range across a variety of behavioral health issues, including depression, substance abuse and domestic violence.

* "Gender Specific Issues of Aging and Chronic Diseases" takes its mandate from the fact that the fastest-growing segment of the U.S. population is women over the age of 65.

Susan Greenspan, director of the Osteoporosis Prevention and Treatment Center and a professor of medicine, leads this team in the investigation of chronic diseases in elderly women, including cardiovascular disease, osteoporosis, arthritis, cancer, diabetes and urinary incontinence.

BIRCWH seeks to increase the number of researchers working on women's health issues by pairing junior researchers with senior investigators to work in mentored, interdisciplinary scientific settings.


Exposure to alcohol before birth means height, weight deficits even at age 14

Children exposed to alcohol in the womb continue to show effects of that exposure even at age 14, Pitt researchers report.

Further, the results indicate that pregnant mothers who consume considerably less than an average of one drink per day put their children at risk for growth deficits and that exposure, as early as the first trimester, increases that likelihood.

The study, published in the October issue of the journal Alcoholism: Clinical and Experimental Research, is among the first to follow the development of children with prenatal alcohol exposure into adolescence.

"Our findings indicate timing is very important for prevention efforts," said principal investigator Nancy L. Day, professor of psychiatry, pediatrics and epidemiology at the School of Medicine. "Children of mothers who drank at least one drink a day during their first trimester weigh up to 16 pounds less, on average, than children with no exposure."

The study found that by the age of 14, children whose mothers drank during pregnancy fell behind in weight, head circumference, height and skinfold thickness compared with those whose mothers abstained. The size of the growth deficits was directly related to the amount of alcohol consumed. The clinical implications for the children's long-term health are not clear, but the growth deficits could serve as a potentially permanent marker of prenatal alcohol exposure. This report did not look at impairments in IQ or other functioning.

The study is one of few that have followed children born to drinking mothers past early adolescence. Mothers were recruited for the study in their fourth prenatal month. These women were then interviewed at regular intervals throughout pregnancy, and then with their children after birth and as the children grew.

Day and her colleagues report there was a substantial decrease in alcohol consumption during pregnancy. Although 38 percent of the women drank one or more drinks per day prior to pregnancy, by the first trimester only 18.9 percent of them drank at the same rate. By the third trimester, only 4 percent reported drinking at the same level.

There were significant differences in alcohol use by race, income level and presence of an adult male in the household. In the first trimester, whites were more likely to drink heavily than were African Americans. However, the white women were more likely to decrease or abstain from drinking later in pregnancy, so that by the third trimester, heavy drinkers were predominantly African American. Monthly income level was lowest among the heavier drinkers and abstainers and highest among the light and moderate drinkers. Light drinkers had the highest proportion of males in the household. The effects of prenatal exposure were still significant after considering these differences.

The study is part of the Maternal Health Practices and Child Developmental Project, a longitudinal study of pregnancy outcomes.


NIH awards professor $1.26 million

Christopher Niyibizi, an associate professor in the Ferguson Laboratory for Orthopaedic Research in Pitt's Department of Orthopedic Surgery and Cell Biology and Physiology, has been awarded a $1.26 million grant by the National Institute of Health.

His study, "Stem Cell Therapy for Diseases of Bone in a Mouse Model," aims to evaluate use of adult bone marrow derived stem cells for the treatment of a brittle bone disease called Osteogenesis Imperfecta (OI).

The study's co-investigator is Janey Whalen, assistant professor in Pitt's urology department. The project also includes consultants Paul Robbins, professor of molecular genetics and biochemistry and director of the Vector Core Facility at Pitt, and Molly Vogt, a Pitt associate professor of orthopaedic surgery and epidemiology, and Jeffrey Hollinger of Carnegie Mellon University.

Osteogenesis Imperfecta is a heterogeneous group of connective tissue disorders whose hallmark is bone fragility. Most forms of OI result from mutations that affect the genes that encode the polypeptide chains of a major collagen of bone and other connective tissues called type I. Many pharmacological agents have been tried for the treatment of OI without much success with exception of bisphosphonates, which have recently been shown to provide some relief. These drugs, however, do not alter the nature of the mutation.

This study will utilize a mouse model of the disease that exhibits clinical features mimicking a severe form of the human OI, to investigate the use of bone marrow derived stem cells for OI treatment and other bone related conditions. Previous studies have shown that mesenchymal stem cells isolated from bone marrow and infused into recipient animals persist in bone and differentiate into osteoblasts, the cells responsible for the synthesis of the entire bone extracellular matrix.

Niyibizi's studies are expected to lead to the design of human clinical trials using bone marrow derived stem cells for treating not only OI but also other bone related diseases such as osteoporosis.


Cancer pain control may be possible with gene therapy

By "programming" a herpes simplex virus to deliver a gene-mediated pain-blocking protein at the cellular level, Pitt researchers have significantly reduced cancer-related pain in mice with tumors, the researchers report in the November issue of Annals of Neurology.

"Chronic pain is notoriously difficult to treat effectively," said co-author Joseph Glorioso, chairperson of the Department of Molecular Genetics and Biochemistry and director of the Molecular Medicine Institute at Pitt's School of Medicine, and president of the American Society of Gene Therapy.

The investigators are pursuing necessary approvals to begin a clinical trial in patients with severe pain resulting from metastatic cancer.

"We are excited about the possibility that this approach may help to control pain in patients who can't get complete relief from the maximum current treatment," said senior author David Fink, a Pitt professor of neurology and molecular genetics and biochemistry and chief of neurology and director of the Geriatric Research Education and Clinical Center at the Veterans Administration Pittsburgh Healthcare System.

Fink, Glorioso and their colleagues created an inactivated herpes simplex virus that carries the human gene for proenkaphalin, a naturally occurring painkilling peptide, a combination of amino acids.

Mice with tumors received injections with the altered virus showed a substantial and significant reduction in pain-related behavior, the authors report.

"Although we have many powerful medications to treat pain, unwelcome side effects of these drugs limit our ability to relieve the most severe painful conditions," Fink said. "Using the virus to deliver the natural painkilling peptide may help in those cases."

Side effects can include excessive drowsiness, constipation and difficulty urinating.


Grant received to develop cell-based strategy for transplant tolerance

Researchers from Pitt's Thomas E. Starzl Transplantation Institute have been awarded $2.3 million from the National Institute of Allergy and Infectious Diseases to explore whether a special type of immune system cell can help induce immune tolerance in kidney transplantation.

Researchers will try to harness a subset of dendritic cells that have unique tolerance-enhancing qualities to see whether the cells can be directed to influence the acceptance of transplanted donor kidneys, including kidneys that are immunologically mismatched to the recipient.

The studies, which will focus on nonhuman primates, are based on other animal research and evidence in transplant patients successfully weaned off all immunosuppression that show a subpopulation of dendritic cells might play a key role in convincing the immune system to accept a transplanted organ.

"It is everyone's goal working in the field of transplantation to identify ways to promote the permanent, drug-free acceptance of transplanted organs," said principal investigator Angus W. Thomson, professor of surgery and immunology at Pitt and the Starzl Transplantation Institute.

The grant builds on several findings that have been reported in recent years by Thomson and his research team.

In one set of studies, a pre-transplant infusion of these dendritic cell subtypes, which derive from lymphoid tissue or blood, allowed for prolonged survival in a mouse heart transplant model, even without the use of drugs to control rejection. In contrast, the better-known myeloid dendritic cells accelerated the rejection response.

According to the researchers, transplant patients who are off immunosuppression have fewer of these type of dendritic cells normally associated with rejection than transplant patients who are prone to rejection or who rely on anti-rejection drugs to maintain their transplanted organ. They also appear to have more of the "good" dendritic cells, according to the Pitt researchers.

Dendritic cells, a rare type of white blood cell that is present in all tissues, are known for their ability to identify and present antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen. Until recently, they have been thought only to be involved in prompting the rejection process. But the subtype of dendritic cells apparently has the opposite effect by regulating the immune response and determining that a frontline attack against the organ by T cells is unwarranted. T cells are the soldiers for the immune system that take their cue from other key cells.

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