Researchers at the University of California, San Diego School of Medicine have discovered that FDA-approved anti-psychotic drugs possess tumor-killing activity against the most aggressive form of primary brain cancer, glioblastoma. The finding was published in this week’s online edition of Oncotarget.
The team of scientists, led by principal investigator, Clark C. Chen, MD, PhD, vice-chairman, UC San Diego, School of Medicine, division of neurosurgery, used a technology platform called shRNA to test how each gene in the human genome contributed to glioblastoma growth. The discovery that led to the shRNA technology won the Nobel Prize in Physiology/Medicine in 2006.
“ShRNAs are invaluable tools in the study of what genes do. They function like molecular erasers,” said Chen. “We can design these ‘erasers’ against every gene in the human genome. These shRNAs can then be packaged into viruses and introduced into cancer cells. If a gene is required for glioblastoma growth and the shRNA erases the function of that gene, then the cancer cell will either stop growing or die.”
Chen said that one surprising finding is that many genes required for glioblastoma growth are also required for dopamine receptor function. Dopamine is a small molecule that is released by nerve cells and binds to the dopamine receptor in surrounding nerve cells, enabling cell communication.
Abnormal dopamine regulation is associated with Parkinson’s disease, schizophrenia, and Attention Deficit Hyperactivity Disorder. Because of the importance of dopamine in these diseases, drugs have been developed to neutralize the effect of dopamine, called dopamine antagonists.
Following clues unveiled by their shRNA study, Chen and his team tested the effects of dopamine antagonists against glioblastoma and found that these drugs exert significant anti-tumor effects both in cultured cells and mouse models. These effects are synergistic when combined with other anti-glioblastoma drugs in terms of halting tumor growth.
“The anti-glioblastoma effects of these drugs are completely unexpected and were only uncovered because we carried out an unbiased genetic screen,” said Chen.
“On the clinical front, the finding is important for two reasons,” said Bob Carter, MD, PhD, chairman of UC San Diego, School of Medicine, division of neurosurgery. “First, these drugs are already FDA-cleared for human use in the treatment of other diseases, so it is possible these drugs may be re-purposed for glioblastoma treatment, thereby bypassing years of pre-clinical testing. Second, these drugs have been shown to cross the blood-brain barrier, a barrier that prevents more than 90 percent of drugs from entry into the brain.”
Chen is now working with the UC San Diego Moores Cancer Center Neuro-Oncology team to translate his findings into a clinical trial.
UC San Diego researchers say risks are manageable, provided doctors recognize them
In the first study of its type, researchers at the University of California, San Diego School of Medicine have looked at the health threat to pregnant women with a history of Kawasaki disease (KD), concluding that the risks are low with informed management and care.
The findings are published in the March 6, 2014 online edition of the British Journal of Obstetrics and Gynaecology.
KD is a childhood condition affecting the coronary arteries. It is the most common cause of acquired heart disease in children. First recognized in Japan following World War II, KD diagnoses are rising among children in Asia, the United States and Western Europe. Predictive models estimate that by 2020 one in every 1,600 American adults will be affected by KD.
“A growing number of women with a history of KD are reaching child-bearing age, but there is little information available to guide their obstetrical care,” said study author Jane C. Burns, MD, professor and director of the Kawasaki Disease Research Center at UC San Diego and Rady Children’s Hospital-San Diego. “By and large, KD is virtually unknown among working obstetricians.”
KD is currently diagnosed by a constellation of clinical signs, with supporting lab tests that indicate high levels of inflammation. These signs include abrupt onset of high fever, accompanied by four of five criteria, among them: widespread rash, cracked and fissured lips, “strawberry tongue,” bloodshot eyes, lymph node enlargement and red, swollen hands and feet.
Without treatment, 25 percent of children with KD develop coronary artery aneurysms – balloon-like bulges of heart vessels – that may eventually result in heart attacks, congestive heart failure or sudden death. The condition can be treated with a high-dose of intravenous immunoglobulin and aspirin, reducing the risk of aneurysms to 5 percent. The long-term risk for adults with a history of KD in childhood is not known.
Senior study author John Gordon, MD, and colleagues conducted the first KD study of non-Japanese patients, and the first to explore the health risks to women with a history of KD and their offspring. They found that the health risks for mothers with no KD-related coronary artery damage were similar to the general population. For women with aneurysms, the risks were low with appropriate management and care.
“The main message is positive,” said Burns. “Women who have had KD can successfully deliver to term without complications. C-sections are not necessarily indicated if they have aneurysms, they can labor normally, if their overall cardiovascular status is OK.”
There is a genetic component to KD. The study found that two of the 21 children born to the 10 women with a history of KD also developed the disease. “There is clearly an increased risk in offspring,” said Burns, “but the (study) numbers are small so we cannot really calculate a risk until there is a larger population of KD adults who have had children.”
Uterine fibroids are noncancerous growths of smooth muscle tissue in the uterus and extremely common. One in four women will experience them, typically in their child-bearing years. They aren’t life-threatening, but they can be enormously debilitating, causing heavy menstrual bleeding, pelvic pain, bladder problems and more.
There are treatments – drugs that release or block specific hormones and various types of surgery. The only current, 100 percent effective remedy for fibroids is a hysterectomy, which involves removing the uterus and results in sterilization. Of the estimated 600,000 hysterectomies performed annually in the United States, about 250,000 are due to fibroids.
In recent years, researchers have explored other approaches, including radiofrequency ablation in which MRI-directed sound waves are targeted at the fibroids, heating them and destroying fibroid cells. In time, the body reabsorbs the dead cells and the fibroids shrink.
We asked Shira Varon, MD, assistant clinical professor in the Department of Reproductive Medicine at the UC San Diego School of Medicine, to talk about new uterine fibroid treatments. Varon and colleagues are currently enrolling participants in a clinical trial of a new outpatient fibroid treatment.
Question: What causes fibroids? How does a woman know she has them?
Answer: Fibroids are the most common pelvic tumor in women and arise secondary to both genetic and hormonal factors. Women should suspect fibroids if they have symptoms of heavy or abnormal periods or pelvic pain or pressure.
Q: What are the shortcomings of currently available treatments?
A: Currently available surgical therapies, especially for women who still desire fertility, are limited to myomectomy (surgical removal of fibroids), which is usually performed via an open surgical procedure. Less commonly, if the patient is a candidate based on the location and size of her fibroids and skill of the surgeon, a myomectomy can be performed with a minimally invasive surgical procedure.
Q: Does radiofrequency ablation hurt?
A: RF ablation, or RFA, is a minimally invasive laparoscopic procedure that has a similar recovery and pain profile to a laparoscopic tubal ligation.
Q: What’s known about the long-term effects of RF? Once a woman has had fibroids, is she likely to get them again?
A: We are currently studying long-tern effects of RFA. The data that we have has followed patients for two years after having the procedure. It appears to be very safe without harm to the surrounding uterus. Whether or not a woman gets fibroids again depends upon her age at the time of the procedure, genetic factors and hormonal factors.
February is National Cancer Prevention Month. A recent published study discusses ovarian surgery—known as prophylactic oophorectomy—as a prevention tool for ovarian and breast cancer. Lisa Madlensky, PhD, director of the UC San Diego Family Cancer Genetics Program, discusses the study and…
Study suggests training kids to pay less attention to food might help them eat less
Among the multiple factors that can cause obesity is an abnormal neurocognitive or behavioral response to food cues. The brain becomes wired to seek – and expect – greater rewards from food, which leads to unhealthful overeating.
Attention modification programs, which train a person to ignore or disregard specific, problematic cues or triggers, have been used effectively to treat cases of anxiety and substance abuse. In a novel study published this week in the journal Appetite, Kerri Boutelle, PhD, professor of pediatrics and psychiatry at the University of California, San Diego School of Medicine, and colleagues report using a single session of attention modification to decrease overeating in obese children.
“Attentional bias is a long-studied psychological phenomenon,” said Boutelle. “Attentional bias to food means that food grabs a person’s attention. If two people were in a room with potato chips on the table, the person with attentional bias would be paying attention to, maybe looking at, the chips and the person without the bias would not really notice or pay attention to them.
“We believe that there is a group of people who are inherently sensitive to food cues and, over time, eating in response to paying attention to food makes them pay even more attention. It’s based on Pavlovian conditioning.”
Obesity in the United States is a well-documented problem, with more than a third of American adults considered to be obese. Child obesity is equally alarming, with an estimated one-third of American children (4 to 5 million individuals) overweight or obese. These children are at greater risk for cardiovascular disease, cancer, orthopedic and endocrine conditions and more likely to die earlier.
Boutelle and colleagues investigated whether attention modification training might be another way to treat problematic eating and obesity in children. In a novel pilot study, they recruited 24 overweight and obese children between the ages of 8 and 12 and split them into two groups
One group underwent an attention modification program (AMP) in which they watched pairs of words quickly flash upon a computer screen. One was a food word, such as “cake;” the other was a non-food word, such as “desk.” After the words had flashed and disappeared, a letter appeared on-screen in the place of either the food word or the non-food word. The viewing child was asked to immediately press the right or left button associated with the letter’s location.
“This is called ‘implicit training’ as it happens so fast that some people might not realize what is happening,” said Boutelle. “The AMP trained attention away from food words because the letter always appeared in the spot of the non-food word while in the other group, the condition trained attention was split with the letter appearing half of the time in the food word location and half in the non-food word location.”
The two computer programs differentially affected eating in the overweight children after only one training session. “It’s surprising to find differences in eating after just one training program,” said Boutelle, “but it’s encouraging because it suggests that a longer program might have greater effect.”
Boutelle said she hopes the pilot study will spawn larger and longer similar investigations, which could ultimately provide another means of addressing overeating and obesity. “Assuming attentional bias training is effective in larger studies, it could be provided in the form of a computer game which could be a stand-alone program or it could potentially enhance their ability to stick to a diet by decreasing the attention paid to food.”
According to the World Health Organization, one-third of cancer cases are preventable. Today, in honor of National Cancer Prevention Month, Ruth Patterson, PhD, discusses a study aimed at preventing recurrence of breast cancer. In our next post, a patient writes about her experience in this…
In a study published in the January 31, 2014 issue of Science, an international team led by scientists at the University of California, San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.
Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP – the largest such cohort assembled to date. The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.
“After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an ‘HSP-ome,’ a map that included all of the new and previously described causes,” said senior author Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego.
The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers were also interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis.
“Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments,” said Gleeson.
“I believe this study is important for the neurodegenerative research community,” said co-lead author Gaia Novarino, PhD, a post-doctoral scholar in Gleeson’s lab. “But more broadly, it offers an illustrative example of how, by utilizing genomics in specific patient populations, and then building an ‘interactome,’ we greatly expand knowledge around unknown causes of disease.”
“This is very exciting since identifying the biological processes in neurological disorders is the first step toward the development of new treatments,” agreed co-lead author Ali G. Fenstermaker. “We identified several promising targets for development of new treatments.”
In studying the impact of DNA damage on the Golgi, a research team from the University of California, San Diego School of Medicine and the Ludwig Institute for Cancer Research have discovered a novel pathway activated by DNA damage, with important consequences for the body’s cellular response to chemotherapy.
Standard cancer treatments, including many chemotherapy drugs and radiation therapy, act on cells by causing DNA damage. In many cancer cells, DNA damage turns on signaling pathways that lead to cell death – the basis of the use of these treatments for cancer.
A better understanding of the signaling pathways that are activated in cells in response to DNA damage, and the influence they exert to determine the fate of the cell to live or die, ultimately could lead to more effective use of these DNA damaging agents to treat cancer.
A study published in the January 30, 2014 issue of the journal Cell – led by Seth Field, MD, PhD, associate professor of medicine at UC San Diego School of Medicine – demonstrates that DNA damage triggers dramatic reorganization of the Golgi. The Golgi serves as the cell’s processing center for the exportation of proteins, lipids and other large molecules to their final destinations outside of the cell. The researchers showed that, in mammalian cells, DNA damage triggers the Golgi to fragment and disperse throughout the cell.
In 2009, the research team had discovered a three-way interaction between a particular Golgi protein, GOLPH3, a lipid signaling molecule, PtdIns(4)P and a contractile protein, MYO18A. The link between the three applies a tensile force required for effective formation of the tubules and vesicles necessary for extracellular transportation.
Later screening identified GOLPH3 as an oncogene overexpressed in many human cancers, which can transform cells into tumorous cells. This study shows that common cancer therapeutic agents, by triggering DNA damage, activate GOLPH3.
“We are honored to be among the top 5 percent of hospitals in the U.S. that demonstrate health system wide, demonstrably superior, clinical quality outcomes,” said Paul Viviano, CEO, UC San Diego Health System. “As the only academic health system in San Diego County, we are devoted to offering unparalleled quality of care and exceptional clinical results based on a philosophy that combines world-class clinical expertise in a patient-centric environment.”
Researchers at University of California, San Diego School of Medicine report a three-fold increase in the use of minimally invasive surgery (MIS) across the nation for patients with pancreatic disease. Although adaptation of MIS for this difficult-to-reach gland is recent, the growing trend points to improved patient outcomes, such as reduced bleeding and infections. Now published online, the paper will appear in the March print edition of JAMA Surgery.
“For the first time, we show a nationwide tripling of keyhole pancreatic surgery rates for benign and malignant pancreatic disease from 2.4 percent in 1998 to 7.3 percent in 2009. Both laparoscopic and robotic approaches for distal pancreas removal are associated with lower rates of inpatient complications and shorter hospital stays,” said Jason Sicklick, MD, assistant professor of surgery, UC San Diego School of Medicine, and surgical oncologist at UC San Diego Health System. “Patients should know that select approaches for minimally invasive pancreatic operations are safe depending upon the lesion’s size and location in the pancreas.”
“We are honored to be listed with our nation’s very best for the innovative care and advanced treatment options we offer in obstetrics and gynecology,” said Thomas Moore, MD, chair of the Department of Reproductive Medicine. “As the only academic hospital in San Diego, our patients have access to a wide range of experts ranging from gestational diabetes and high-risk pregnancies to pelvic floor disorders and menopause.”
Eleven California hospitals made the list, two of which are University of California based medical centers.
A study led by researchers at the University of California, San Diego School of Medicine shows that one of the most widely used systems for predicting risk of adverse heart events should be re-evaluated. A surprise finding was that coronary artery calcium (CAC) density may be protective against cardiovascular events. The study of CAC will be published in the January 15 issue of the Journal of the American Medical Association (JAMA).
“Current scoring systems assume that denser heart plaque (CAC) is more hazardous, but we found the opposite,” said Criqui. “It’s not good to have CAC but it is less hazardous if it’s more dense.”
The standard CAC score is called the Agatston. According to the National Heart, Blood and Lung Institute, the score is based on the amount of calcium found in a patient’s coronary arteries. Traditionally, the test is negative if no calcium deposits, or calcifications, are found in the arteries, and interpreted to mean that the chance of the patient having a heart attack in the next 2 to 5 years is low.
The test is positive if calcifications are found in the arteries. Calcifications are a sign of atherosclerosis, a condition in which the arteries harden and narrow due to plaque buildup. The higher the Agatston scores are, the more severe the atherosclerosis.
“However, our study shows that in addition to CAC volume, the role of CAC density should also be considered when developing a risk score,” Criqui said. “A greater volume of CAC does indicate a higher risk, but at any given volume of CAC, a higher density is associated with lower risk. This may be because densely calcified plaques are more stable.”
New veterinary and comparative medicine center advances health care, human and otherwise
Discoveries about how diseases arise or are transmitted in animals can be useful in understanding the same sorts of afflictions in humans. Similarly, new therapies or techniques used in people may be effective in caring for animals as well.
The newly established Center for Veterinary Sciences and Comparative Medicine (CVSCM) at the University of California, San Diego School of Medicine embodies this ideal – a highly integrated and innovative consortium of universities, institutions, scientists, physicians and veterinarians seeking to improve the condition of all animals, human and otherwise.
“By understanding the biology of disease, either in people or in animals, all benefit,” said Peter Ernst, DVM, PhD, professor of pathology at UC San Diego School of Medicine and founding CVSCM director. “We want to use the lessons learned and advances made in human healthcare to improve the lives of animals and vice versa.”
It builds upon UC San Diego’s long-standing post-doctoral training program in laboratory animal and comparative medicine and has close links to the UC Veterinary Medical Center-San Diego, a collaboration between UC San Diego Health Sciences and the UC Davis School of Veterinary Medicine.
Many CVSCM scientists are on the leading edge of their research disciplines, investigating mucosal infections and immune responses, gastrointestinal ailments such as inflammatory bowel disease or celiac disease, parasite transmission, cancer and neurodegenerative diseases involving prions and misfolded proteins – the last affecting humans, cows, deer and other animals.
Ernst said creating the CVSCM boosts the ability of veterinary scientists to tap into the larger and better-funded world of human health research. “We will have access to greater resources, improved collaboration with other physicians and scientists and more exposure to new and different trials, projects, techniques and technologies. We can learn new tricks.”
The CVSCM is not a veterinary service, Ernst noted, but rather an effort to advance the care of animals – and humans – through new, unprecedented efforts in research and training for graduate veterinarians. “We are committed to the idea of one health/one medicine,” he said.
“The focus of the Bridging Hearts and Minds Conference is to create connections between the classroom, laboratory, therapy room and living room to foster the study and practice of mindfulness for the good of the next generation,” said Steven D. Hickman, PsyD, executive director of the UC San Diego Center for Mindfulness. “The mindfulness movement is impacting the psychological, physical and the social well-being of young people globally by helping to reduce stress, increase focus and positively impact school performance. This conference will help attendees learn how to achieve these results in their own communities.”
Technology Improves Accuracy of Device Placement and Patient Outcomes
The interventional cardiology team led by Ehtisham Mahmud, MD, FACC, at UC San Diego Sulpizio Cardiovascular Center (SCVC) has successfully completed the first two robotically-assisted coronary angioplasty/stent procedures in California. Patients with coronary artery disease (CAD) now have access to this new technology that puts the precision of a robot in the hands of interventional cardiologists during procedures to open clogged heart arteries.
The CorPath System designed by Corindus Vascular Robotics (Natick, MA), offers interventional cardiologists unparalleled control in catheterization laboratories (cath labs) while performing coronary angioplasty and stenting.
“Sitting a few feet away from the patient’s bedside at a computerized work station, I was able to navigate and advance the guidewire, balloon catheter and stent through the coronary artery. The ability to accurately measure lesion length with this technology enabled me to identify the exact length of the stents required and precisely place them,” said Mahmud, chief of cardiovascular medicine and director of the SCVC-Medicine.
The first patient treated was a 66-year-old woman who had previously undergone coronary artery bypass graft surgery and required stenting of a 90 percent blockage in her native artery. The second patient was a 61-year-old man with a severe 95 percent blockage of his right coronary artery who presented with unstable angina.