Because of STAT-6s potential medical importance, pharmaceutical scientists have tried to find small molecules or compounds to act as therapeutics to stop the function of STAT-6. Their search has not been successful.
To better understand the STAT-6 pathway and attempt to identify other putative targets for therapeutic intervention to prevent asthma and allergy, the laboratory of Dr. Paul Rothman, Richard J. Stock Professor of Medicine (Immunology) and Microbiology, a year ago decided to take a multigenic approach. His laboratory compared the genes activated or repressed by STAT-6 in immune cells using microarray technology, which takes a snapshot of all the genetic activity inside a cell affected by STAT-6, rather than focusing on the expression of STAT-6 alone.
The researchers led by Dr. Rothman analyzed the gene expression profiles of IL-4-activated B-cells, which make the IgE antibody that cause allergies and asthma. These cells were isolated from mice with and without the STAT-6 gene. The researchers found 31 genes expressed at higher levels in cells expressing STAT-6. Surprisingly, the researchers found that STAT-6 also acts as a repressor of many genes. They found 39 genes that were expressed at higher levels in IL-4-activated B-cells lacking the STAT-6 gene.
The result implies both positive and negative regulatory functions of STAT-6 in IL-4-mediated gene expression, says Dr. Rothman, who also is chief of the division of pulmonary, allergy, and critical care medicine. The regulatory pathway of STAT-6 is quite complex.
His laboratory is now following up on these findings. The team had identified several proteins that had not been known to be involved in the IL-4-based immune response. They are also using microarray technology to study the gene expression profiles in mice missing other relevant genes in the pathway.
The research results were published in the Feb. 1 issue of the Journal of Immunology. Working with Dr. Rothman on the study were Dr. J. Andreas Schroeder, a postdoctoral research fellow; Dr. Paul Pavlidis, associate research scientist in the Columbia Genome Center; Akinori Arimura, a visiting scientist from Japan; and Danielle Capece, a technician.
Conferees noted that adults who abuse alcohol and drugs are more likely to have casual sex partners, and teens who use alcohol and drugs are more likely to have had sex at younger ages and with more partners. Also, people who abuse alcohol and use drugs have higher rates of sexually transmitted diseases, including HIV and AIDS; most prostitutes are alcohol and drug abusers; and alcohol is a common companion to date rape.
Panelists suggested that part of the reason behind the substance abuse and sex link is that people, including youngsters, lose inhibitions when under the influence of alcohol and drugs and would be more likely to engage in risky sexual behavior. In other cases, some people just take more risks, either sexually or with drugs or alcohol.
Sexual abuse early in life also may lead to self-destructive behavior later. Conferee Dr. Maureen Miller, assistant professor of epidemiology at the Mailman School of Public Health, spoke about how, in her research, she has seen that victims of sexual molestation often later turn to drugs. Once girls who are sexually abused become aware that such abuse is not a normal situation, they frequently find themselves doing drugs, Dr. Miller said.
Drug abuse also can lead to risky sex. Dr. Miller, who also is studying drug addicts in New York City, observed that women drug addicts will use sex to either acquire more crack cocaine or get the money to pay for the drug. Selling themselves is not what they want to do but they do it because of limited employment opportunities, Dr. Miller said.
How can the problem be fixed? Addressing sexual issues in addiction programs and substance abuse in sexual education can help, said Joseph Califano, CASA chairman and president and adjunct professor of health policy and management (in psychiatry) at Mailman.
The Henry J. Kaiser Family Foundation and the National Institute on Drug Abuse co-sponsored the conference with CASA.
But a recently completed clinical study from the laboratory of Dr. Richard L. Whelan, associate professor of surgery, and other P&S investigators provides molecular evidence that suggests the traditional operation, done via a single lengthy incision (open method), might lead to more cancer recurrences than laparoscopic surgery.
The study, which was presented Feb. 16 at the Society of University Surgeons, demonstrated that plasma from patients who had undergone major open surgery was depleted of a protein that inhibits tumor growth. The protein is insulin-like growth factor binding protein 3 (IGF-BP3). Plasma from patients with comparable laparoscopic operations had higher levels of the protein after the operation. Preoperative IGF-BP3 levels were similar in both groups of patients.
By virtue of their higher IGF-BP3 levels, laparoscopic patients may be better able to prevent tumor cells, which might remain in the bloodstream after surgery, from forming tumor metastases, Dr. Whelan says.
In the study, plasma samples from 84 patients who underwent either colectomy or gastric bypass for obesity were collected before and after surgery; 45 of the operations were open and 39 laparoscopic. The majority were colectomy patients with colon cancer. The plasma samples were added to tumor cells growing in vitro; 48 hours later, the number of tumor cells in each well was determined. The researchers found that the open patients postoperative plasmas were significantly more mitogenic than their preoperative plasmas. No differences in tumor growth were noted when the laparoscopic groups plasma was similarly assessed.
The results of several other experiments suggested that decreased levels of IGF-BP3 was the cause of the increased tumor growth observed with the open postop plasma. Addition of IGF-BP3 to open patients postop plasma lowered the tumor cell growth rate to the level observed with the preop plasma. Further, the addition of antibodies to IGF-BP3 to preop plasma increased the mitogenic effect of the plasma.
Whether IGF-BP3 has any impact on long-term survival is unknown. Dr. Whelan and his collaborators are performing further studies in mice to see if giving the animals IGF-BP3 before surgery might in some way prevent the in vitro cancer cell proliferation that occurs with the plasma collected after open surgery.
Drs. Irena Kirman, Kenneth A. Forde, Marc Bessler, and Anthony Oh and Vesna Cekic, Natalia Polatratskai, and Zishan Asi participated in the study.