by Tom O’Connor, UNMC public relations

A common question asked by researchers is, “What is the function of my favorite gene?” One way to answer this is to knock it out from the research model – either a cell or an organism.

From left: C.B. Gurumurthy, Ph.D., Rolen Quadros and Don Harms offer the TALENs service through the UNMC Mouse Genome Engineering Core Facility. 

By “knocking out” the gene, researchers can determine the function of the gene by studying the differences between a knocked-out model and a model in which the gene is normal.

Now, thanks to UNMC acquiring a powerful new tool, scientists will be able to knock out genes in their research models very easily. The tool is called TALENs (Transcription Activator-Like Effector Nucleases), and the TALENs service is offered through the UNMC Mouse Genome Engineering Core Facility directed by C.B. Gurumurthy, Ph.D., and his team members, Don Harms and Rolen Quadros.
TALENs are protein tools that work like custom-made DNA cutting scissors.

TALENs that cut and alter any particular gene can be built in less than two weeks. “With TALENs, it is easy to knock out your favorite gene more reliably and much faster than before,” Dr. Gurumurthy said.

He said knocking out a gene is superior to other commonly used approaches such as RNAi, where the gene is only knocked down and the results can be ambiguous. TALENs tools also can be used for creating knockout models of other species other than just the laboratory mouse.

Dr. Gurumurthy said, “The TALENs technology has become a popular method in the past couple years, and many researchers worldwide have been able to learn much more about gene functions using TALENs.” He noted that more than 300 high profile research publications used TALENs in 2012.

“For UNMC to be among the first three universities to launch the TALENs service speaks volumes,” said Paula Turpen, Ph.D., director of research resources. “Guru’s team is always on the forefront of cutting edge technologies and has introduced several services related to gene knockouts and transgenics in the past two years.”

“We can build custom TALENs at much less cost than what it would cost to build TALENs in each individual labs,” Dr. Gurumurthy said.

The service includes bioinformatics analysis of genomic locus, designing and building of TALENs including consultation on how to use TALENs. For more details, contact Dr. Gurumurthy at cgurumurthy@unmc.edu or visit the Mouse Genome Engineering Core Facility website.

Omaha, Neb – Greg Rathe has been here before. Waiting. This time it’s much different than it was 17 years ago. Rathe, 42, said his first heart transplant in 1996 came about after a sudden onset of cardiomyopathy, the weakening of the heart muscles. Early this year, his symptoms returned.

“I felt weak and couldn’t breathe,” Rathe said. ‘When I got here to the med center, they said I’d need a new heart.”

“His condition deteriorated very quickly,” said Mike Moulton, MD , chief of cardiothoracic surgery and heart transplant surgeon at The Nebraska Medical Center.

Rathe lost consciousness the second week in March. His donated heart was failing.

“We knew if we didn’t move forward with the Total Artificial Heart , Greg would not survive,” said John Um, MD , surgical director of cardiac transplantation and mechanical circulatory support at The Nebraska Medical Center.

Drs. Moulton and Um implanted the Total Artificial Heart March 14.

“I woke up and it was all done,” Rathe said.

During heart failure, the heart cannot pump enough blood to supply vital organs with the oxygen and nutrients they need. When one side of the heart is failing, a patient can be put on a left- or right-ventricular assist device . Greg Rathe’s heart needed help on both sides.

“Greg had chronic rejection of his donated heart,” Dr. Moulton explained. “That process affected both the left and right ventricles. Because his heart had deteriorated to such a degree, a Total Artificial Heart was the only option.”

The Total Artificial Heart is not a permanent solution. It is a “bridge to transplant” meaning it can allow a patient to regain their strength until a suitable donor heart is found. It provides high volume blood flow of up to 9.5 liters per minute through each ventricle, which helps speed the recovery of the patient’s organs, making them a better candidate for heart transplant. According to SynCardia , which makes the device, patients have survived nearly four years before receiving a successful transplant. Doctors expect Rathe to have his artificial heart for one to six months.

“The Total Artificial Heart is the most advanced support available,” said Ioana Dumitru, MD , medical director of heart failure and cardiac transplantation at The Nebraska Medical Center. “It can now be used to treat patients from our region who would have a very difficult time traveling long distances to receive this therapy.”
To implant the Total Artificial Heart , surgeons remove most of the patient’s heart; the left and right ventricles and the four heart valves. Only the left and right atria, aorta and pulmonary artery remain. Surgeons then sew in ports called “quick connects” to the left and right atria, aorta and pulmonary artery. The Total Artificial Heart is then attached to the quick connects. Two clear plastic tubes, one connecting to each ventricle, extend through the patient’s skin just below the rib cage. The tubes are connected to a pneumatic driver, which powers the artificial heart with precisely calibrated pulses of air and vacuum. All the device’s motors and electronics are located outside the body in the pneumatic driver. When a donor heart is available, surgeons remove the artificial heart and transplant the donor heart.

The Nebraska Medical Center is the only hospital in Nebraska with this treatment option.

“Bringing the Total Artificial Heart technology to the region continues to demonstrate The Nebraska Medical Center’s leadership and commitment in the treatment of cardiovascular disease,” said Jorge Parodi, executive director of cardiovascular care at the medical center. “We will continue to pioneer new technologies and therapies here and continue to provide the most complete and comprehensive cardiovascular care in this region.”

UNMC oncologist chairs panel that develops new guidelines to help guide adolescents, young adults through cancer

A University of Nebraska Medical Center pediatric oncologist, Peter Coccia, M.D., served as chairman of a national panel that developed patient guidelines to help guide adolescents and young adults with cancer through diagnosis, treatment and after therapy.

These guidelines answer patients and their family’s most common questions related to how to prepare for treatment, what to ask the doctor, and explain the most common medical terms.

“The adolescent and young adult (AYA) group includes individuals between the ages of 15 to 39 and represents a challenging age group for onocologists to treat successfully,” Dr. Coccia said.

The American Cancer Society’s Cancer Journal for Clinicians notes that remarkable progress has been made in the treatment of children under the age of 15 and in adults over 40 years of age in the last 35 years, but there has been minimal improvement in the survival rate in the 70,000 new AYA patients with invasive cancer diagnosed yearly.

The guidelines were developed through the National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 21 of the world’s leading cancer centers dedicated to improving the quality and effectiveness of care provided to patients with cancer. The UNMC Eppley Cancer Center at The Nebraska Medical Center is a charter member of the NCCN.

The NCCN Guidelines are developed and updated through an evidence-based process in which the expert panel integrates comprehensive clinical and scientific data with the judgment of the multidisciplinary panel members and other experts drawn from NCCN member institutions. Access to the NCCN Guidelines for Patients or any of the NCCN Guidelines is available free of charge at NCCN.com.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives.

The NCCN member institutions are: City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women’s Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Memorial Sloan-Kettering Cancer Center, New York, NY; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; UNMC Eppley Cancer Center at The Nebraska Medical Center, Omaha, NE; The University of Texas MD Anderson Cancer Center, Houston, TX; and Vanderbilt-Ingram Cancer Center, Nashville, TN.

Patients who have experienced stroke or a transient ischemic attach (TIA) are at significant risk for another stroke. In many cases, a TIA is a warning sign that a true stroke may happen in the future if something is not done to prevent it.

“Preventive surgery can reduce the risk of a future stroke 9 to 26 percent a year,” says William Thorell, MD, neurosurgeon at The Nebraska Medical Center.

“Now physicians have two safe and effective options for treating carotid artery disease, the traditional carotid revascularization endarterectomy or carotid stenting,” says Dr. Thorell. “In the past, endarterectomy was thought to be the preferred procedure. However, recent evidence produced by the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) revealed similar results in patients for the treatment of carotid stenosis.” Results were published in the July 2010 issue of the New England Journal of Medicine.

“The morbidity and mortality are about equivalent for both at approximately 5 percent,” says Dr. Thorell. Complications include stroke, heart attack and death. In this particular trial, the death rate was extremely low, at just .3 to .7 percent.

A patient who presents with symptoms of a stroke or TIA, should undergo imaging in the cerebral vessels. This can be done with ultrasound, MRA or CTA.

If the scan reveals narrowing of the carotid arteries by 50 percent or more, the patient should be seen by a specialist to determine if he or she is a candidate for surgery. “We work as a team with our vascular surgery colleagues to determine which procedure is most appropriate for the patient,” says Dr. Thorell. “In certain situations, stenting is preferable to endarterectomy. This includes patients who have had previous radiation surgery to the head and neck, patients who have had a previous endarterectomy with recurring narrowing and patients with difficult anatomy for surgery.”

While many patients are prescribed drugs like statins, blood pressure medications and anti-platelet agents such as Aggrenox to reduce their risk of stroke, surgical treatment of severe blockages in the carotid artery has been shown to be more effective than medical therapy alone in preventing ischemic strokes caused by plaque buildup.

Stroke is the third leading cause of death and the number one cause of disability in adults, with 750,000 new strokes occurring each year.

A rise in the incidence of certain head and neck cancers among middle-aged Americans and their link to the human papilloma virus (HPV) is leading some medical experts to begin recommending the HPV vaccine for both men and women.

“The last decade has seen a 5 to 6 percent increase per year in the incidence of cancers of the tonsils and base of the tongue,” says William Lydiatt, MD, a head and neck cancer specialist at The Nebraska Medical Center, “and it is primarily due to the human papilloma virus (HPV). Sixty to 70 percent of all tonsil cancers in the U.S. are HPV-related.”

Recent studies also indicate there may be a link between these cancers and having multiple sex partners and oral sex, says Dr. Lydiatt. A 2007 study in the New England Journal of Medicine found that younger people with head and neck cancers who tested positive for oral HPV infection were more likely to have had multiple vaginal and oral sex partners in their lifetime. However, half of these individuals had fewer than five sex partners, he says.

Approximately 80 percent of sexually active women and 75 percent of men harbor the HPV virus. In men, it is usually asymptomatic.

These HPV-related cancers are two times more common in men than women. While still fairly rare among the population as a whole compared to other cancers, the rising incidence is beginning to reach epidemic proportions, says Dr. Lydiatt. Currently, approximately 12,000 Americans will be diagnosed with cancers of the tonsil or base of the tongue each year with 8,000 being men and 4,000 women, he says. “It’s now comparable to the same rate as cervical cancer,” says Dr. Lydiatt.

With numbers on the rise, Dr. Lydiatt recommends that both young men and women receive the HPV vaccine called Gardasil, which has been approved by the Food and Drug Administration (FDA) to prevent cervical and anal cancers.

The good news is that even at stage IV, these individuals have a very high cure rate, says Dr. Lydiatt. The typical patient is a white, non-smoking male in his 50s who presents with a sore in the throat, which will not heal or a painless neck mass just below the jaw line. The patient may complain of difficulty eating, swallowing and talking. Other symptoms include ear pain, change in voice, sore throat, bleeding gums, bad breath and an altered sense of taste. An early symptom that may be detected during a clinical exam is an asymmetry of the tonsil, notes Dr. Lydiatt.

Tonsil cancer can spread very quickly and metastasize to other parts near the throat. A neck mass should be evaluated if it does not go away in one week. Based on clinical suspicion, a CAT scan should be considered followed by a biopsy of the tonsil, tongue or neck mass, says Dr. Lydiatt.

If a positive diagnosis is found, patients with these types of cancers have the best outcomes with a comprehensive, multi-disciplinary approach to treatment because of the nature of the disease and the substantial affects treatment can have on a person’s basic aspects of living including their ability to eat, drink, swallow, taste and talk, says Dr. Lydiatt. The Nebraska Medical Center uses a multi-disciplinary approach that includes a combination of oncologists, radiation oncologists, dental oncologists, head and neck surgeons, speech and swallowing specialists, nutritionists, nurses and social workers. Some patients may also need psychosocial counseling to prevent depression because of the physical changes they may experience to the facial and neck areas.

Cardiac MRI is a very powerful diagnostic tool and one of the most valuable techniques available to image the heart, says Samer Sayyed, MD, cardiologist at The Nebraska Medical Center and assistant professor of Internal Medicine at the University of Nebraska Medical Center (UNMC).

“Cardiac MRI goes beyond just analyzing the structure of the heart, but can also provide accurate quantitative assessment of bi-ventricular and valvular function, shunt fraction, myocardial perfusion, viability and scarring, as well as angiography of the pulmonary and systemic vasculature, all while avoiding the use of ionizing radiation or contrast agents that are toxic to the kidney,” he says.

First line cardiac diagnostic studies generally involve an electrocardiogram and/or an echocardiogram. A cardiac MRI study is appropriate when other tests are inconclusive, or when additional information about a patient’s cardiac condition is required to develop a more accurate diagnosis or management plan, notes Dr. Sayyed.

To get the most value from an MRI, the exact indication for ordering the test needs to be provided so the study can be tailored to effectively answer the clinical questions at hand, says Dr. Sayyed. “The study itself can take anywhere from 30 minutes to over an hour sometimes,” he says, “therefore, time is of the essence, and it is not a test to be performed in emergency situations.”

Some of the primary indications for cardiac MRI include:

• Assessment of cardiac structure and function when other techniques are insufficient or ineffective
• Evaluation of valvular structure and function
• Cardiac stress testing
• Assessment of myocardial viability prior to revascularization
• Ischemic and non-ischemic cardiomyopathy such as hypertrophic cardiomyopathy, sarcoidosis, amyloidosis, and hemochromatosis.
• Cardiac masses or thrombi
• Complex congenital heart disease
• Aortic and pulmonary angiography for aneurysms/dissection even for those who can’t receive contrast
• Complex intra and extra cardiac shunts
• Arrhythmogenic right ventricular dysplasia
• Pericardial disease such as acute pericardial inflammation and pericardial constriction

A comprehensive list of appropriate, uncertain, and inappropriate indications for cardiac MRI has been published by the Journal of the American College of Cardiology in 2006, says Dr. Sayyed.

It should also be noted that the contrast agents used for cardiac MRI are very different from those used for CT scans, says Dr. Sayyed. A CT scan uses an iodine-based agent whereas a cardiac MRI uses a gadolinium-based agent. The iodine agent can be toxic to the kidneys. The gadolinium-based agent, on the other hand, is not nephrotoxic and can be given to a larger group of patients, even those with moderate kidney disease. However, it should not be used on those patients with severe kidney disease. Even in those with a contraindication for contrast, there are ways to perform non-contrast enhanced MRI angiography with high image quality, notes Dr. Sayyed.

Because cardiac MRI uses magnetic fields, patients with implanted ferromagnetic material such as pacemakers, nerve stimulators or have a history of welding may not be eligible for this test. Obese and claustrophobic patients may also be unable to fit within the magnet, or tolerate being confined within its bore for the duration of the study. Despite these few limitations, MRI remains the gold standard noninvasive method of evaluating a wide array of cardiovascular diseases.

Early diagnosis and evaluation is key for patients with kidney disease who are candidates for hemodialysis. “Our goal is to evaluate patients well before they need dialysis so we can provide them the proper access and determine if they are candidates for transplant,” says Michael Morris, MD, who heads the Vascular Access Clinic at The Nebraska Medical Center. Dr. Morris and his team specialize in vascular access surgery, laparoscopic procedures and kidney transplantation.

“One of the leading reasons for rehospitalization for these patients is complications related to their vascular access,” he says. Common complications include strictures, infections, aneurysms, clotting and poor blood flow. “Our team has been doing this for many years. We have the experience and expertise to ensure our patients are receiving the correct type of access, the procedure is performed properly and they are cared for and managed appropriately.” Dr. Morris and his team work very closely with nephrologists in the dialysis unit to determine the best solution for each patient and to minimize complications.

“This is a long-term relationship,” says Dr. Morris. “We are committed to the long-term care and health of our patients. “We understand that the loss of vascular access can mean the difference between life and death for our patients.”

Dr. Morris specializes in placing fistulas, which is the most difficult procedure to perform but it is also the most successful with the fewest problems over the long term, he says. Patients require four to six weeks of healing time after surgery before they can begin dialysis. He also performs catheter access procedures, which are intended for short-term use and should be avoided whenever possible as they tend to injure the veins.

Because the clinic is associated with the Transplant Program at The Nebraska Medical Center, patients have the benefit of being evaluated for kidney transplant at the same time they are evaluated for vascular access. “In some cases, we can delay dialysis, and at the very least, get the transplant process started while the patient is on dialysis instead of waiting until the patient is in a dire situation,” says Dr. Morris. This is important because unless the patient has a living donor, the transplant waiting time can be up to several years. Many patients qualify as transplant candidates.

The ultimate goal, notes Dr. Morris, is to avoid dialysis whenever possible and to get a patient on the transplant list. But for this to happen, “we need to see patients well before they need dialysis,” he says. “The risks associated with dialysis tend to be far greater than the risks associated with transplant and transplant patients have longer survival rates.”

Early symptoms of kidney disease include protein in the urine, uncontrollable high blood pressure and serum creatinine.

Dr. Morris is also co-director of the Kidney/Transplant program at The Nebraska Medical Center and associate professor of Surgery at the University of Nebraska Medical Center.

Doctors at The Nebraska Medical Center have added a new high-speed cardiac nuclear imaging camera that can improve doctors’ ability to evaluate a patient’s risk of having a heart attack to their arsenal of cardiac diagnostic tools.

Compared to older nuclear imaging cameras, the new technology offers a solid state technology that results in images of higher quality and can reduce imaging time from approximately 15 to 20 minutes per scan to as low as two to four minutes per scan. As a result, it has the potential to significantly reduce radiation exposure for patients. Additionally, the camera allows patients to be scanned in a much more comfortable, sitting position, than the standard supine position with the arms raised above the head.

“This provides us with another important non-invasive diagnostic tool to risk stratify our patients,” says Kiran Gangahar, MD , cardiologist at The Nebraska Medical Center. “Currently, it is the only high-speed, solid-state, cardiac nuclear imaging camera available in Omaha.”

Nuclear cardiac imaging offers an alternative to patients who are unable to undergo other forms of stress imaging, such as stress echo, because of the inability to image the heart by ultrasound, intolerance to some of the pharmaceutical agents used, physical limitations or body habitus. The test can be used for assessment of ischemia, ejection fraction and myocardial viability.

It is also an effective alternative when echo images are of poor quality. “The time period allowed for echo imaging is much shorter,” says Dr. Gangahar. “With nuclear imaging we have 15 to 30 minutes to take pictures compared to just a few minutes allowed with echo. This allows us to perform multiple pictures to ensure we get the right one.”

In addition, the pharmacological agent used has a shorter half life so it is eliminated from the body much faster so patient tolerance is much better. The testing area can also accommodate obese patients up to 550 pounds as long as the patient is mobile.

Typical candidates for the procedure are those at intermediate risk for coronary artery disease. “These are patients who have risk factors for coronary artery disease, but may have atypical symptoms,” says Dr. Gangahar.

To perform the procedure, the patient is injected with a nuclear tracer fluid based on their body mass index (BMI). The patient’s chest is then imaged in a comfortable sitting position. The patient will then have either an exercise or pharmaceutical stress test, as determined by their physician. This is followed by an imaging post stress in sitting and reclining positions.

“Nuclear stress tests are strong predictors of future cardiac events,” says Dr. Gangahar. “The goal is to identify patients who are at high risk for cardiac events so that further, invasive diagnostic testing such as cardiac catheterization, appropriate medications and aggressive risk factor modification can be implemented.”

by John Keenan, UNMC public relations

 
UNMC remains the sixth-ranked primary care medical program in the United States, according to the 2014 U.S. News & World Report rankings of the nation’s top graduate schools.

“To be recognized as a leader in primary care is a testament to the tremendous work of all our faculty, staff and students at UNMC,” Chancellor Harold M. Maurer, M.D., said. “Our expertise in primary care will be particularly beneficial to our state and region in the coming years, as more emphasis is placed on wellness and preventive care, and the need increases for more primary care providers.”

U.S. News surveyed 149 institutions while compiling the rankings, which were released Tuesday.

In addition to the primary care ranking, UNMC ranked 64th in research.

“To be recognized as a leader in primary care is a testament to the tremendous work of all of our faculty, staff and students at UNMC.”

Chancellor Harold M. Maurer, M.D.

“We’re pleased to see the rankings, which reflect the exceptionally talented faculty, staff and students we have here working on behalf of Nebraska,” said Dele Davies, M.D., vice chancellor for academic affairs. “Our educational mission is vital to everything we do here at UNMC. We strive to ensure our students receive an education that gives patients the best and most innovative care possible.”

Rankings are based on two types of data: expert opinions about program excellence and statistical indicators that measure the quality of a school’s faculty, research and students.

Primary care rankings included a series of indicators such as peer assessment, assessment by residency directors, student selectivity, mean Medical College Admission Test (MCAT) score and other factors.

Although new rankings aren’t available in all categories for 2014, UNMC continues to be rated in four other programs:

16th of 130 physician assistant programs;
32nd of 125 pharmacy programs;
34th of 201 physical therapy programs; and
36th of 467 for the master’s program in nursing.

Effective treatment of multiple sclerosis (MS) begins with early and proper diagnosis. However, the episodic nature of the disease as well as the fact that no two cases are alike can make it difficult to diagnose even in the best hands, notes Mac McLaughlin, MD , an MS-trained neurologist who works at the Multiple Sclerosis Clinic at The Nebraska Medical Center and an assistant professor of Neurological Sciences at the University of Nebraska Medical Center (UNMC).

“Getting the right diagnosis and starting the right medications early in the disease is important for the overall disease outcome,” says Dr. McLaughlin. “If we can get a patient started on medications very early in the disease course, we can maximize the ability to slow down the progression of the disease.”

The use of MRI has greatly improved diagnosis of the disease and has made it possible to diagnose the disease earlier in the disease process. “An MRI image can show areas of active inflammation, which indicates active involvement of MS,” says Dr. McLaughlin.

“Because of the multiple types of medications available in addition to keeping up with the changing symptoms, the disease can be difficult to manage,” says Dr. McLaughlin. “That’s where a multi-disciplinary clinic like ours can really help patients stay on top of the disease to control symptoms and slow the progression.”

The Multiple Sclerosis Clinic is one of the most comprehensive in the region. The clinic, which follows more than 1,500 MS patients, staffs the only two MS-trained medical specialists in the area and is supported by an experienced and dedicated MS staff of physical therapists, case managers and physician assistants. Patients also benefit from the expertise of specialists in areas such as physical and occupational therapy, psychiatry, neuro-ophthalmology, pain, urology and OB/GYN.

The Multiple Sclerosis Clinic provides a comprehensive approach to MS care that addresses the physical, psycho-social and economic situation of each patient. Because MS affects each person differently, treating the whole person and their individual symptoms can make a significant difference in their quality of life, says Dr. McLaughlin. Our clinic is a partner with the patient throughout their lifetime.