RESEARCH
Ronald Weigel, MD, PhD
Overview
The Weigel laboratory has had a long-standing interest in determining mechanisms of hormone response in breast cancer. Our work has identified transcriptional mechanisms that regulate the expression of estrogen receptor-alpha in breast carcinomas. Other areas of investigation have sought to identify genes that are related to hormone response and additional mechanisms of gene regulation that are responsive to estrogen.
Current Projects
- Regulation of ERa by AP2g. We identified the AP2g transcription factor as a key regulator of hormone response in breast cancer. We are now examining mechanisms of gene regulation that involve this transcription factor.
- Chromatin Effects Altering AP2 Activity. We have shown that epigenetic chromatin alterations can influence activity of AP2 at certain promoters. The mechanism appears to involve altered binding of AP2 mediated through chromatin structure. Studies to determine how chromatin structure alters AP2 activity are being pursued.
- Interaction of AP2 and p53. We demonstrated a direct interaction between AP2 factors and the p53 tumor suppressor. The interaction of p53 and AP2 has functional effects on these two factors that appear to alter hormone response in breast cancer and cell growth in other cancer types. We are investigating the details of this interaction and the functional effects on gene regulation and cell physiology.
Current Funding
- R01 CA109294-01 Weigel (PI) 2/01/06-01/31/11
NIH/NCI
Mechanisms of Estrogen Receptor Regulation
This study will elucidate mechanisms regulating AP2-mediated activation of the ERa promoter and hormone response in MCF7 cells, will determine the mechanism of p53-mediated repression of ERa expression and will define the residues involved in the interaction between p53 and AP2 and generate antagonists for this interaction.
Role: Principal Investigator
- C0403 01/01/05-12/31/07
WW Smith Charitable Trust
Rescue of Estrogen Response in Hormone Insensitive Breast Cancer
This project will develop molecules capable of altering the interaction between AP2g and p53 in hormone responsive breast cancer.
Role: Co-investigator
Key Words: hormone response, breast cancer, estrogen receptor
G. Patrick Kealey, MD
Dr. Kealey has participated in a number of research projects at the University of Iowa Hospitals and clinics, more specifically geared toward the burn patient. He has been a PI in projects such as Efficacy of Burn Patient Pressure Garment Therapy sponsored by the International Association of Fire Fighters Burn Foundation. He has also been instrumental in the Establishment of a Burn Survivor Outcomes Database using two health status questionnaires funded by the UI Injury Prevention Research Center. Another project of interest included Randomized Controlled Paired Within-Patient Study to Assess Safety and Efficacy of DermagraftÔ Transitional Covering (Dermagraft TC) in Patients Requiring a Temporary Covering for Deep-Partial or Full-Thickness Thermal or Chemical Burn Injuries funded by the Advanced Tissue Sciences.
Key Words: thermal burns, chemical burns, dermagraft
Kent Choi, MD
Dr. Choi’s interests are:
- Obesity in trauma care outcome and its associated pathophysiology
- Epidemiology of trauma injury prevention
- Surgical infection
- Steroid usage in critical care
Key Words: trauma care, surgical infection, injury prevention
Dionne Skeete, MD
My clinical research projects cover trauma care delivery and surgical critical care.
Key Words: trauma care, surgical critical care
Timothy Light, MD
Research interests include clinical research in trauma and burns.
Key Words: trauma, burns
Barbara Latenser, MD
Dr. Latenser’s recent research has focused on three main areas: abdominal compartment syndrome, necrotizing fasciitis, and methamphetamine injuries.
- Abdominal compartment syndrome is a rare, under-reported problem that affects the most seriously burned and injured patients. Left untreated, it can lead to multi-organ failure and death. The standard treatment procedure, decompressive laparotomy, has a low success rate and mortality rate as high as 80%. Dr. Latenser is currently investigating percutaneous drainage as a safer, less invasive procedure for treating this “silent killer.”
- Burn centers throughout the U.S. are seeing increasing numbers of patients with necrotizing soft tissue infections (NASTI) which present great management challenges. Although historically these patients have mortality rates of 32-52%, early diagnosis and aggressive surgical management has led to a UIHC mortality rate of 5.6%. Confounding factors currently being investigated include the effects of obesity, strict glycemic control, and possible underlying malignancy.
- Methamphetamine (meth) is a highly addictive drug which is easily manufactured from everyday household products and chemicals, leading to a proliferation of small local labs, especially in the Midwest. Dr. Latenser performed a retrospective study at UIHC showing that compared to meth negative patients, the meth positive population had larger burns, stayed in the hospital longer and accrued expensive hospital bills, typically a cost absorbed by the hospital as lost revenue. In conjunction with the Injury Prevention Research Center, Dr. Latenser is working on federal grants that will screen high risk populations in Iowa, evaluate safety for first responders, and evaluate the impact of the Pseudoephedrine Law in Iowa.
Key words: abdominal compartment syndrome, necrotizing fasciitis, methamphetamine injuries
Joseph Cullen, MD
Our research laboratory is focused on developing treatments for pancreatic cancer. Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Our efforts are directed in two specific areas.
- Dicumarol is a naturally occurring anticoagulant derived from coumarin, which is obtained from the sweet clover (Melilotus alba). Though such coumarin compounds as dicumarol have been utilized in cancer therapy, little is known about the mechanism of action of these drugs. Recent studies from our group have demonstrated that dicumarol induces cytotoxicty and oxidative stress in pancreatic cancer cells and this cytotoxicity appears to be more prominent in transformed vs. normal human fibroblasts. Mitochondria have been hypothesized to be the site of proxidant production during dicumarol treatment since dicumarol is thought to affect quinone-mediated electron transfer reactions leading to the production of superoxide (O2.-), and hydrogen peroxide (H2O2). Dicumarol-induced oxidative stress could represent a difference between tumor cell and normal cell mitochondrial metabolism amenable to manipulations designed to improve cancer therapy. To gain a mechanistic understanding of dicumarol-induced oxidative stress in pancreatic cancer cells, our laboratory investigates the hypothesis that mitochondrial production of reactive oxygen species (superoxide, hydrogen peroxide, and/or organic hydroperoxides) mediates the increased susceptibility of pancreatic cancer cells to dicumarol-induced metabolic oxidative stress, relative to normal human cells.
- The objective of our second set of studies is to determine if antioxidant enzymes can be modulated for therapeutic purposes in pancreatic cancer. Signaling through the K-ras pathway in pancreatic cancer is related to treatment resistance. K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Ras overexpression leads to increased plasma membrane-generated superoxide, which could be one mechanism regulating cell growth contributing to tumor progression. The objective of our studies is to determine if plasma membrane-generated superoxide can be modulated for therapeutic purposes in pancreatic cancer. Our central hypothesis is that scavenging of superoxide generated from the plasma membrane inhibits pancreatic cancer growth. Our hypothesis has been formulated on the basis of data demonstrating that scavenging of superoxide with the antioxidant enzymes extracellular superoxide dismutase (ECSOD) and copper/zinc superoxide dismutase (CuZnSOD), and small molecule superoxide scavengers have a strong tumor suppressive effect in pancreatic cancer.
It is our expectation that the results will facilitate the discovery and development of targeted therapeutics against pancreatic cancer.
Our laboratory is currently partially funded by grants from the National Institutes of Health.
Key words: reactive oxygen species, dicumarol, oxidative stress, pancreatic cancer, antioxidant enzymes, free radical biology
Kimberly Ephgrave, MD
Medical Education: Current projects
- A multi-institutional, multi-disciplinary survey of clerkship directors as P.I. of an Alliance for Clinical Education project looking at the resources available to clerkship directors for student education, relative to the national guidelines, and relative to their perceived effectiveness
- Outcome analysis of a medical student program for clinical students to reflect on their professional development and any ethical/problematic clinical issues they observed
- Analysis of disciplinary actions against medical school graduates
- Assessment of learning needs for medical school faculty
- Factors associated with medical school graduates choosing not be board-certified
- Assessment of professionalism across levels of training and medical discipline
Surgery
Past projects include randomized trials of stress ulcer prophylaxis, outcome analysis of feeding enterostomies, colon screening, time of year in academic centers, and treatment of pancreatic pseudocysts, multiple studies of stress ulceration and gastric motility in various animal models.
Key Words: medical student education, professionalism training, stress ulcer prophylaxis
Isaac Samuel, MD
Samuel Lab: Acute pancreatitis pathogenesis:
The laboratory investigates the role of acinar cell signaling pathways such as the stress kinase (p38, JNK, ERK) pathway and the Akt/NFkB pathway as applied to a novel hypothesis for gallstone pancreatitis pathogenesis. The role of pancreatic hyperstimulation via G-protein coupled receptors (CCK receptor and cholinergic receptor) and their regulation by a novel group of proteins called RGS (regulation of G-protein signaling) proteins are also being investigated. Our long-term goal is to elucidate the pathogenesis of acute pancreatitis with a view to implement new treatment modalities. Current funding from NIH is a NIDDK K08 Career Development Award.Samuel Clinical Research:
Measurement of physical activity and energy expenditure in bariatric surgery patients to improve pre-operative evaluation and long-term post-operative outcomes.Key Words: pancreatitis, bariatric surgery
Carol Scott-Conner, MD, PhD
- Breast cancer during pregnancy; specifically epidemiologic studies of the interaction of pregnancy and breast cancer. Studies of a variety of cancers using the National Cancer Database. I currently chair the Upper Gastrointestinal (Gastric) Subcommittee of the NCDB and direct studies through this entity.
- Advisory to NASA for health care issues related to long duration missions beyond Earth orbit through the Institute of Medicine.
Key words: cancer, breast cancer, pregnancy, women, gastric cancer, space flight
Neal Wilkinson, MD
Research Interest and Current Projects
- Examination of the National Cancer Bata Base registry for pattern of presentation and treatment between subgroups of gastric cancer
- Examine pooled Analysis of recurrence pattern and survival NSABP trials examining control and 5FU/LV based arms
- Exploratory study of chemotherapy induced hepatic damage treated at UI: pathology and clinical outcomes study
- Retrospective review of portal venous gas treated at the UI reporting cause, treatment and outcome
- Retrospective review of pancreatic cancer at UI 1995-present
Key Words: NSABP, pancreatic cancer, gastric cancer
James Howe, MD
Work in the Surgical Oncology Molecular Biology lab is focused upon understanding and defining the genetic basis of Juvenile Polyposis (JP). The main objective of our current studies is to identify the third causative gene for this inherited cancer predisposition syndrome. To this end, a large Iowa JP family is being tested using a comprehensive panel of genetic markers derived from all the human chromosomes to determine the chromosomal location of this gene. When candidate genes from this region are found, they will be tested for mutations in this JP family, and a panel of over 90 different JP families. In addition to this research focus, we have also been studying how the mutations in people born with JP lead to the formation of polyps. To do this, we have taken both normal and polyp tissues obtained from surgery or endoscopy in JP patients with mutations in the three different JP genes. From these we have performed microarray analysis, which allows us to compare the level of expression of all human genes. These patterns of changes in gene expression between the different JP genes will help us to understand which genetic pathways are involved in polyp development. We are also systematically examining the effects of the DNA mutations in JP patients upon the RNA messages and protein products that result from them. To do this, we have established cell lines from the white blood cells from a large number of JP patients, which gives us a repository of renewable cells for future studies. This will help to clarify the effects of mutations in some JP patients, while in others in whom no mutations have been found by sequencing, may suggest alterative mechanisms of how the JP genes are inactivated. It will also make in vitro studies possible, which will give us a way to determine the effects of various drugs on cells, so that we may develop treatments that will suppress the development of polyps and cancers.
Key Words: juvenile polyposis, genetic markers, polyps
Geeta Lal, MD
My lab is interested in studying genetic markers that can be used for diagnosis and in predicting prognosis of thyroid cancer and other endocrine malignancies. We also maintain an endocrine tumor tissue bank. We are also involved in several clinical projects in endocrine surgical oncology
Key Words: thyroid cancer, endocrine malignancy, genetic markers
Timothy F. Kresowik, MD
My research activities are in the area of physician and hospital performance measures. My work dates back to 1993 and has involved a number of national performance measurement projects with the Centers for Medicaid and Medicare Services (CMS) and the American Medical Association (AMA). Most recently I have been a facilitator/consultant for all the performance measurement workgroups of the AMA sponsored Physician Consortium for Performance Improvement (PCPI). This includes measures that have been developed in the following clinical areas; Adult Diabetes, Anesthesiology, Asthma, Atrial Fibrillation, Child and Adolescent Major Depressive Disorder, Chronic Kidney Disease (CKD), Chronic Obstructive Pulmonary Disease (COPD), Chronic Stable Coronary Artery Disease (CAD), Community-acquired Bacterial Pneumonia, Emergency Medicine, End Stage Renal Disease (ESRD), Eye Care, Gastroesophageal Reflux Disease (GERD), Geriatrics, Heart Failure, Hematology, Hepatitis C, Hypertension, Major Depressive Disorder, Osteoarthritis, Osteoporosis, Otitis Externa / Otitis Media with Effusion, Outpatient Parenteral Antimicrobial Therapy, Pediatric Acute Gastroenteritis, Perioperative Care, Prenatal Care, Preventive Care and Screening, Prostate Cancer, Skin Cancer, Stroke and Stroke Rehabilitation. The measures currently proposed for the CMS Physician Voluntary Reporting Program (PVRP) are derived almost entirely from these measure sets. I am also the UIHC physician lead for implementation of the National Surgical Quality Improvement Program (NSQIP) which is a risk adjusted surgical outcome measurement project.
My future interest is in the development and testing of point of care standardized electronic data collection and decision support to facilitate performance measurement reporting and quality improvement. The goal would be to avoid the need for any retrospective data collection in addition to maximizing performance.
Key words: performance measurement, quality improvement, outcomes
Jamal Hoballah, MD
Dr. Hoballah’s research focuses on clinical problems in vascular surgery. One challenging topic is the management of ruptured abdominal aortic aneurysms and the associated problems related to abdominal compartmental hypertension. Currently the experience at the University of Iowa with ruptured abdominal aortic aneurysm is being reviewed with special attention to the management of abdominal compartmental hypertension and its effect on renal perfusion and management by open abdomen.
Another clinical issue that is being evaluated is the value of screening and surveillance of the abdominal aorta and the carotid arteries in patients presenting with lower extremity occlusive disease or in patients undergoing coronary artery bypass surgery. Another research interest is the management of acute limb ischemia. This continues to be a very challenging problem with respect to revascularization using surgical techniques versus endovascular techniques with lytic therapy. This is especially true due to the changes in available lytic therapy drugs. The experience with the use of lytic therapy in the management of acute arterial occlusion is currently being investigated to determine the group of patients that would benefit most form such an approach versus who would benefit more from surgical reconstruction.
One additional topic is the management of chronic arterial insufficiency as manifested by intermittent claudication. The current therapy is limited to an exercise program and one drug therapy. A new industry trial is focusing on the use of a new drug in the management of intermittent arterial claudication.
The endovascular treatment of infrainguinal occlusive disease remains a controversial and challenging topic. The newer devices have become more available, including a new atherectomy device. The treatment of patients with infrainguinal occlusive disease using the new modality of atherectomy has been used in an isolated group of patients. The outcome of atherectomy is being re-evaluated in the long term and compared to other endovascular methods of therapy.
Keywords: abdominal aortic aneurysm; intermittent claudication; acute limb ischemia; endovascular therapy.
Daniel Katz, MD
Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial (BENEFIT- IM103008) and Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial- Extended Criteria Donors (BENEFIT-EXT IM103027) Bristol-Myers Squibb
Belatacept (LEA29Y) represents a new class of immunosuppressive for use in renal transplantation. Belatacept is an immunomodulator that selectively inhibits costimulation of T-cells.
The purpose of these two pivotal studies is to evaluate the effects of belatacept compared with cyclosporine on renal function and graft survival in kidney transplant recipients (IM103008) and in ECD kidney transplant recipients (IM103027).
The primary objectives will be to evaluate the composite subject and graft survival by 12 months, the composite of measured GFR at month 12 or a decrease in measured GFR from month 3 to 12, and the incidence of acute rejection by month 12.
Both studies are three-year phase III, multi center, randomized, partially-blinded, active controlled, parallel group study comparing three regimens: more intensive (MI) belatacept, less intensive (LI) belatacept, or cyclosporine. All will receive background therapy with basiliximab and maintenance with MMF and steroids. Belatacept is administered as a ½ hour infusion every two weeks for the first three months, then monthly until the end of the three year study.Belatacept Conversion Trial in Renal Transplantation (IM103010) Quintiles
This trial is in the early start up phase and is currently pending. The trial will study the conversion of patients from a standard immunosuppressive regimen to a Belatacept based regimen.A 24-month, multicenter, randomized open-label non-inferiority study of efficacy and safety comparing concentration-controlled Certicanâ in two doses (1.5 and 3.0 mg/day starting doses) with reduced Neoralâ versus 1.44 g Myforticâ with standard dose Neoralâ in de novo renal transplant recipients. Novartis
Certican (everolimus, RAD001) is rapamycin derivative for renal transplant indications.
The purpose of this study is to examine the impact of Certican with reduced Neoral dose on efficacy failure and renal function relative to Myfortic with standard dose of Neoral.
The primary objective is to compare the composite efficacy failure rate (treated BPAR, graft loss, death, loss to follow up).
Subjects will be randomized 1:1:1 to receive one of the two Certican doses with reduced dose Neoral or Myfortic with standard dose Neoral. Therapeutic drug monitoring will be performed to maintain the protocol required Neoral and Certican trough levels. All groups will receive background therapy with Simulect and steroids according to local practice.A retrospective study of en-block and split pediatric kidney transplant and outcomes at UIHC. Investigator initiated
The purpose of this study is to collect and analyze the data from UIHC patient record for pediatric en-block and split pediatric kidney transplant under the donor age of 5 yrs. A retrospective data collection will be done for all the UIHC and affiliated sites for pediatric kidney transplant and analysis will be done for result, outcomes and efficiency of en-block and split pediatric kidney transplant from the donors under the age of 5 years. After analysis and result of these data we are hoping that we can increase procurement of kidneys for donation from the pediatric age group, increase the use of pediatric kidneys for organ transplantation, future clinical studies and ultimately increase renal graft survival rates, particularly those procured from children. There is recent evidence to suggest that en bloc kidneys have better long-term function than split pediatric kidneys. This observation may not be universal, but may be biased by center experience. We would like to extend our investigation to the national data set. Exploring the hypothesis that there is no center effect on pediatric kidney outcome comparing split and en bloc kidneys is relevant to the transplant community because acceptance or rejection of the hypothesis will have ramifications on organ allocation and usage.
What is the effect hepatocellular tumor down staging prior to liver transplant? Investigator initiated
In patients with cirrhosis, liver transplantation is indicated as a potentially curative therapy for patients with stage I and II hepatocellular carcinoma (HCC). Although initially controversial, multiple reports now demonstrate that five-year post transplant patient survival for cirrhotics with small tumors is similar to survival among patients undergoing transplant without cancer. Therefore, the transplant community as sanctioned by the United Network for Organ Sharing (UNOS) grants MELD (model for end stage liver disease) exception points to patients with small HCC in order to improve their status on the waiting list. However, patients with stage III and IV tumors have been found to have worse long term outcomes due to tumor recurrence. Reflective of the poorer outcomes, UNOS does not grant exception points to patients with tumors exceeding stage II. Most centers are reluctant to transplant patients with higher stage tumors due to poor outcomes, and doing so as a practical matter has become difficult without the benefit of MELD exception points.
Several reports now indicate the feasibility of obtaining acceptable post transplant outcomes for some stage III and IV patients who are treated with pretransplant transarterial hepatic chemoembolization (TACE), radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), or a combination of these modalities. Therefore, there is some support in the literature for expanding the UNOS stage restrictions and also for the utility of tumor down staging or treatment prior to transplant. There is the additional concern of tumor growth while awaiting transplant. If a tumor grows beyond the UNOS size requirements while the patient is waiting for transplant then the exception points are withdrawn. Pretransplant tumor treatment is therefore employed as a strategy to prevent waiting list dropout due to tumor growth.
At the University of Iowa pre-liver transplant tumor treatment has been used to downstage tumors into parameters that are acceptable to obtain MELD exception points and also to prevent wait list dropout. It is not known if pretransplant treatment of larger stage tumors affords survival that is equivalent to standard criteria tumors or if treatment is necessary to prevent waitlist dropout. The purpose of this retrospective review is to analyze the outcomes of patients whose tumors have been treated prior to transplant and compare these outcomes with those among patients who received no tumor treatment prior to transplant.New initiatives to Maximize Benefits from Pediatric Kidney Donors. Investigator initiated
The focus of this project is to study factors that may improve use of pediatric donor organs.
The first aim of this project is to develop an effective protocol for the identification of neonatal and pediatric organ donors and achieve excellent consent rates. The second aim is to implement and test the administrative and surgical protocols that we have developed for heart-beating and non-heart-beating neonatal and pediatric organ donors. The third aim is to develop preliminary data on stress-activated protein kinases (SAPKs) in the pathogenesis of renal ischemia-reperfusion injury that may play a role in pediatric transplant failure.
In summary, in Aim One we intend to increase procurement of kidneys for donation from the pediatric age group, in Aim Two we propose to increase the use of pediatric kidneys for organ transplantation, while in Aim Three we will begin pilot experimental studies that will lead to future clinical studies and ultimately increase renal graft survival rates, particularly those procured from children.Key Words: immunosuppression, renal transplantation, liver transplantation
Joel Shilyansky, MD
Dr. Shilyansky studies the immune response in pediatric cancer patients. Specifically the mechanism allowing cancers to avoid immune destruction are being addressed. By understanding these mechanisms vaccines that can induce anti-cancer immunity and lead to cancer regression may be developed. Dendritic cells, white blood cells that regulate the immune response, are critically important for effective anti-tumor responses. Cancer cells appear adept at inhibiting dendritic cells. Recent studies in the laboratory examined phosphatidylserine as a mechanism for inhibiting dendritic cells and for evading tumor immunity. Phosphatidylserine is a membrane phospholipid that is normally restricted to the inner surface of the cell membrane (envelope) and is exposed on the cell surface during programmed cell death (apoptosis). However, live cancer cells can express phosphatidylserine on the cell surface. Dr. Shilyansky’s laboratory has demonstrated that tumor phosphatidylserine inhibits human peripheral blood derived dendritic cells. Phosphatidylserine appear to interfere with NF-kappaB and p38 MAPK activation, signaling events required for dendritic cell maturation and function. Recent work has concentrated on the in vivo mechanisms by which phosphatidylserine affects tumor immunity. Additional studies in Dr. Shilyansky’s laboratory relate to cancer vaccine development and effects of ligating CD40, a critical receptor on antigen presenting cells, in tumor immunity.
Key Words: pediatric cancer patients, tumor immunity, cancer vaccine