Scientists show bad androgen receptor impairs body’s ability to dispose of damaged cells
Researchers at University of California, San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility.
The study, published August 10 in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy’s disease impairs the body’s ability to degrade, remove and recycle clumps of “trash” proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins.
“We’ve known since the mid-1990s that Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over,” said senior author Albert La Spada, MD, PhD and professor of pediatrics, cellular and molecular medicine, and neurosciences. “The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function.”
Of the 400 to 500 men in the U.S. with Kennedy’s disease, the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheel-chair bound during later stages of the disease.
Kennedy’s disease, also known as spinal and bulbar muscular atrophy, is a recessive X-linked disease men inherit from their mother. Women don’t get the disease because they have two copies of the X chromosome. The genetic abnormality causes men to produce a mutant androgen receptor protein, which impairs the body’s sensitivity and response to male sex hormones, sometimes resulting in testicular atrophy and enlargement of male breasts.
In experiments with mice, scientists discovered that the mutant androgen receptor protein besides disrupting male reproductive biology also deactivates a protein called transcription factor EB (TFEB) that is believed to be a master regulator of autophagy in nerve and other cell types.
Specifically, the mutant androgen receptor protein in Kennedy’s disease binds to TFEB and blocks its ability to mediate the break-down and removal of non-working proteins and aggregated proteins.
“Our study tells us that if we can find a way to keep TFEB working, we likely can prevent this disease and others like it from progressing,” La Spada said. “We now have a target for new therapies to treat not only Kennedy’s disease, but also many more common neurological disorders.”
Regional project awarded nearly $6 million Health Care Innovation grant
Approximately 84 million people in the United States suffer from some form of cardiovascular disease, and about 720,000 Americans have a heart attack every year, which works out to one every 44 seconds. To address these alarming statistics, the Be There San Diego Initiative has been awarded a $5.8 million Health Care Innovation grant for a coalition project to help reduce heart attacks and strokes in San Diego County.
The Initiative’s program, San Diego: A Heart Attack and Stroke Free Zone, is a regional collaboration of health care organizations and stakeholders to improve health care delivery and patient outcomes.
The goal during the three year project is to enroll 4,000 high risk patients and lower their blood pressure and cholesterol levels through evidence-based practices and a better understanding of the importance of treatment adherence. The project will also promote heart attack and stroke prevention measures, test novel, cost-effective technology solutions and provide educational opportunities both for patients and within the physician community.
Partners in the Be There Initiative include UC San Diego Health System, Arch Health Partners, Scripps Health, Sharp HealthCare, Kaiser Permanente, Palomar Medical Center, Naval Medical Center, Veterans Administration, the San Diego County Medical Society Foundation, the County of San Diego Health and Human Services Agency, community clinics and others. UC San Diego Health System serves as the fiscal agent for the project.
“Health organizations that are competitive in the market will be working together for the benefit of San Diego patients,” said Anthony DeMaria, MD, principal investigator of the Heart Attack and Stroke Free Zone program and cardiologist at UC San Diego Health System. “This approach will decrease our community’s risk for cardiovascular disease and could result in saving millions in the county by preventing half of the heart attacks and strokes that would have otherwise occurred in the participating patient population.”
Only 20 institutions garner top designation on Hospitals & Health Networks’ annual survey
UC San Diego Health System is among the nation’s “Most Wired Advanced” hospitals, according to new findings released by Hospitals & Health Networks (H&HN), a publication of the American Hospital Association. The designation – given to just 20 of 375 hospitals cited – highlights institutions that have most effectively leveraged information technologies to improve performance and patient care.
The 16th Annual Health Care’s Most Wired Survey covers 1,900 hospitals, roughly one-third of the nation’s total. It evaluates how hospitals use information technologies in five areas: business processes, customer service, safety and quality, workforce and public health, and safety. It identified 375 hospitals and health systems, ranging in size from 25 beds to more than 10,000, as “most wired.” Seventeen are based in California.
A University of California, San Diego School of Medicine-led study suggests that parents of obese children often do not recognize the potentially serious health consequences of childhood weight gain or the importance of daily physical activity in helping their child reach a healthy weight.
The study is published online in the Journal of the Academy of Nutrition and Dietetics.
“Parents have a hard time changing their child’s dietary and physical activity behaviors,” said lead author Kyung Rhee, MD, and an assistant adjunct professor in the Department of Pediatrics. “Our study tells us what factors may be associated with a parent’s motivation to help their child become more healthy.”
The study is based on a survey of 202 parents whose children were enrolled in an obesity clinic at the Hasbro Children’s Hospital in Providence, Rhode Island in 2008 and 2009. The survey probed parents’ readiness to take actionable steps to improve their child’s eating habits and physical activity levels. The children ranged in age from 5 to 20 years old, with an average age of 13.8 years. More than two-thirds were female, and almost all (94 percent) were clinically classified as obese.
Although most of the children had been referred to the obesity clinic by a primary care provider and had metabolic markers of obesity, 31.4 percent of parents perceived their child’s health as excellent or very good and 28 percent did not perceive their child’s weight as a health concern.
Parents indicated a greater interest in helping their child eat a healthy diet than encouraging the pediatrician-recommended hour of daily physical activity.
Specifically, 61.4 percent of parents reported that they were improving their child’s eating habits (less junk food, more fruits and vegetables) while only 41.1 percent said they were increasing their child’s involvement in active play, sports, dancing or even walking. Both diet and exercise are considered keys to good health, and a growing body of evidence suggests that these health habits are formed early in life.
Parents who had talked with their primary care physician about healthy eating strategies were more likely to be in the “action stage of change” with their child’s diet. By contrast, parents who viewed their own battle with weight as a health concern were less likely to be addressing their child’s eating habits.
The researchers said education, income and race/ethnicity had no statistically significant bearing on a parent’s likelihood of making dietary changes for their child.
In terms of physical activity, researchers do not know why parents appear to under-emphasize its role in good health, but the finding is consistent with other recent studies that suggest America’s youth are largely out-of-shape and sedentary, replacing playtime with “screen time.”
Experts say one strategy to counteract the trend may be to intervene early. Parents with children 14 or older were much less likely to be successful in helping their child develop a physical dimension to their life than parents of younger children.
Poverty may also play a role in how much children move on a daily basis, as parents with annual incomes of less than $40,000 were also less likely to be actively engaged in ensuring their child got regular exercise.
Researchers at the University of California, San Diego School of Medicine have documented the safety benefits of aortic stent grafts inserted during minimally invasive surgery to repair abdominal aortic aneurysms – weaknesses in the body’s largest artery that can rupture, causing potentially lethal internal bleeding.
The study, published July 9 in JAMA Surgery, shows that patients who received the minimally invasive aortic repair procedure had a 42 percent reduction in preventable post-operative complications and a 72 percent reduction in mortality, compared with those who had undergone open repair surgery.
The safety of the endovascular “inside blood vessel” procedure also appears to be improving over time, as researchers documented a 37 percent reduction in the likelihood of an avoidable complication between 2003 and 2010.
The statistics are based on an analysis of 70,946 cases of abdominal aortic aneurysm repair performed over the seven-year period, culled from a nationwide hospital database maintained by the Healthcare Cost and Utilization Project.
“All this is good news for patients because endovascular repair has become the most common treatment for abdominal aortic aneurysms,” said senior author John Lane, MD, director of Endovascular Surgery at UC San Diego Health System and associate professor at the UC San Diego School of Medicine.
Surgeons call for national safety measures to protect patients
Researchers at the University of California, San Diego School of Medicine have found that the risk of patient harm increased two-fold in 2006 – the peak year that teaching hospitals nationwide embraced the pursuit of minimally invasive robotic surgery for prostate cancer. Results of the study are published in the July 2 online issue of JAMA Surgery.
“This study looked at the stages of innovation and how the rapid adoption of a new surgical technology—in this case, a surgical robotic system—can lead to adverse events for patients,” said Kellogg Parsons, MD, MHS, surgical oncologist, UC San Diego Health System and first author of the paper. “There is a real need for standardized training programs, rules governing surgeon competence and credentialing, and guidelines for hospital privileging when novel technologies reach the operating rooms of teaching and community hospitals.”
In 2003, there were an estimated 617 minimally invasive robotic prostatectomies (MIRPs) performed in the United States. By 2009, this number increased to 37,753 procedures. In 2005, patients were twice as likely to experience an adverse event if they were undergoing MIRPs compared to a traditional open surgical procedure. The following year –2006 – was considered the tipping point for the adoption of MIRP when it equaled or exceeded 10 percent of all cases.
“The trend observed here is not new to robotic surgery. The same phenomena occurred with the move to minimally invasive approaches to gallbladder and kidney surgeries, both surgeries that are now well documented to improve safety and outcomes,” said Christopher Kane, MD, professor of surgery and interim chair of the Department of Surgery, UC San Diego School of Medicine, who was not involved with the study. “Whenever a new technology is adopted there is a temporary period where there may be an increased risk to the patient. This can be reduced by extensive surgical training, vigorous credentialing standards and extended mentorship by experienced surgeons. This report should encourage the adoption of more rigorous credentialing standards proposed by professional organizations rather than by individual hospitals.”
Kane added that robotic prostatectomy by experienced surgeons has proven to be beneficial to the patient with less blood loss, reduced infections and shorter hospital stays.
“A responsibility of deploying a surgical technology should include the responsibility to monitor it as it diffuses throughout the real world to ensure safety,” said David C. Chang, PhD, MPH, MBA, director of Outcomes Research at UC San Diego School of Medicine and the paper’s senior author. “Surveillance of surgical safety should be ongoing, much like the Centers for Disease Control monitor changes in trends of infectious diseases across the country.”
The UC San Diego team used Patient Safety Indicators, developed by the Agency for Healthcare Research and Quality (AHRQ), to develop a nationwide data sample to analyze surgical provider performance and potential in-hospital adverse events from 2003-2009. Data for the prevalence of robotic prostatectomy was pulled from AHRQ and compared to published data from Intuitive Surgical Inc., the manufacturer of the da Vinci robotic system.
“One potential intervention would be the development of standardized training and credentialing programs, much like the aviation industry requires of flight crews inexperienced with new types of aircraft,” said Parsons, who is also an associate professor of surgery at UC San Diego School of Medicine. “An independent, continuously updated tracking system for the adoption of new surgical technology is also essential. Prior estimates of robotic prostatectomy uptake, provided exclusively by the robot manufacturer, substantially overestimated the speed with which it was adopted by the surgical community.”
In a bizarre twist, Cyclin D, long believed to promote cancer, actually activates tumor suppressor
Researchers at the University of California, San Diego School of Medicine say a protein essential to regulating cell cycle progression – the process of cell division and replication – activates a key tumor suppressor, rather than inactivating it as previously thought.
“The finding is the result of literally 20 years of work in my lab,” said Steven F. Dowdy, PhD, professor in the Department of Cellular and Molecular Medicine at UC San Diego. “It completely turns upside-down what was thought to be a fundamental aspect of cell cycle progression in all cancer cells driven by one of the most common genetic pathways mutated in cancer, namely the p16-cyclin D pathway.”
The findings are published in the journal eLife.
Cyclin D is synthesized during the first stage of cell replication and is believed to help drive the complex, multi-stage process, including interaction with the retinoblastoma (Rb) protein, whose function is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. Rb acts as a tumor suppressor.
But mutated or dysfunctional Rb is associated with several major cancers and Cyclin D has long been described as an oncogene that promotes cancer because it was believed to inactivate the Rb tumor suppressor function through a process called phosphorylation, which involves phosphate molecules being added to proteins, essentially turning them on or off.
Dowdy and colleagues painstakingly counted the number of phosphates added to Rb during cell cycle progression. There are as many as 14, but the scientists found that cyclin D adds just a single phosphate at one, and only one, of the 14 locations during the early G1 phase of cell cycle progression, essentially make 14 different versions of the Rb tumor suppressor. The single phosphate serves to activate Rb, not inactivate it as had been thought for over 20 years.
The researchers said the findings fundamentally change the understanding of G1 cell cycle regulation and the molecular origins of many associated cancers. It is critically important to understand how a genetic pathway actually functions and the consequences of interrupting it, especially in this case where there are multiple drug inhibitors of cyclin D being tested in clinical trials for breast cancer.
Moreover, how the next cyclin, cyclin E, that actually does inactivate Rb becomes activated has not been heavily investigated because it was thought to be the less important second domino, whereas we now know it is the first domino, added Dowdy.
“Every patient diagnosed with glioblastoma is treated with a chemotherapy called temozolomide. About 15 percent of these patients derive long-lasting benefit,” said Clark C. Chen, MD, PhD, vice-chairman of Academic Affairs, Division of Neurosurgery, UC San Diego School of Medicine and the study’s principal investigator. “We need to identify which patients benefit from temozolomide and which another type of treatment. All therapies involve risk and the possibility of side-effects. Patients should not undergo therapies if there’s no likelihood of benefit.”
To pinpoint which patients were most likely respond to temozolomide, the researchers studied microRNAs that control the expression of a protein called methyl-guanine-methyl-transferase or MGMT. This protein dampens the cancer-killing effect of temozolomide. Tumors with high levels of MGMT are associated with a poor response to temozolomide therapy.
The scientists systematically tested every microRNA in the human genome to identify those that suppressed MGMT expression, with the expectation that high-levels of these microRNAs in the tumor would predict improved therapeutic response to temozolomide.
“We showed that a signature of the MGMT-regulating microRNAs predicted temozolomide response in a cohort of glioblastoma patients. Validation of these results should lead to diagnostic tools to enable us to determine which patients will benefit most from temozolomide therapy,” said Chen.
In the study, the scientists also discovered that injection of the MGMT-regulating microRNAs into glioblastoma cells increased tumor sensitivity to temozolomide treatment.
“These findings establish the foundation for microRNAs-based therapies to increase the efficacy of temozolomide in glioblastoma patients,” said lead author, Valya Ramakrishnan, PhD, postdoctoral researcher, UC San Diego School of Medicine.
Effective July 1, 2014, James H. McKerrow, MD, PhD, will become the second dean of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego. McKerrow will join UC San Diego from UC San Francisco, where he served as professor of pathology and director of the Center for Discovery and Innovation in Parasitic Diseases.
An expert in the area of neglected tropical diseases, McKerrow brings a wealth of experience in natural product research and drug discovery and development. His keen interest in these areas will help bring together cross-disciplinary researchers at UC San Diego and in the community – in global health, infectious diseases, biology and chemistry and drug development programs – all of which are of strategic importance to the Health Sciences and the UC San Diego campus.
New ultrasound procedure can identify blockages in fallopian tubes
Many women struggling to become pregnant may suffer from some degree of tubal blockage. Traditionally, an x-ray hysterosalpingogram (HSG) that uses dye is the most common procedure to determine whether a blockage exists, but it can cause extreme discomfort to the patient. UC San Diego Health System’s doctors are the first fertility specialists in the county to use a new ultrasound technique to assess fallopian tubes by employing a mixture of saline and air bubbles that is less painful, avoids x-ray exposure and is more convenient to patients during an already vulnerable time.
Using the FemVue Sono HSG, the physician delivers the mixture of saline and air bubbles into the uterus through a small catheter, which then flows into the fallopian tubes. Under ultrasound, the air bubbles are highly visible as they travel through the tubes, allowing the physician to determine if a blockage exists.
“The traditional x-ray approach involves higher pressure and usually causes significant cramping as the dye is administered. The anticipated pain prevents some women from even attempting the test. Others cannot do the test because they are allergic to the dye. Assessing the tubes for a blockage is a key component of the diagnostic workup in fertile couples, and not doing so because of pain or allergy is a real concern,” said Sanjay Agarwal, MD, director of Fertility Services in the Department of Reproductive Medicine at UC San Diego Health System. “The new approach is not only much more comfortable for patients, it also uses saline, so the issue of an allergy does not arise. We are also able to assess the cavity of the uterus at the same time - all without x-rays.”
Kristina, a mother who has been trying to conceive a second child for almost a year, agreed: “I was willing to do whatever it took to address the fertility issues we were facing, but after everything we had been through emotionally, it was a relief to undergo a procedure that wasn’t physically painful.”
The ultrasound is performed in the clinic, and at present, ideal candidates include those with a prior pregnancy and those at low risk for tubal disease.
“Like the traditional x-ray HSG, the new test should be performed after the period has ended but before ovulation. The fact that the patient can schedule this ultrasound-based test in the clinic and not in radiology prevents a delay in care and allows the patient’s physician to be more involved in the process,” said Agarwal, also director of the UC San Diego Center for Endometriosis Research and Treatment (CERT).
Kristina said she was scheduled for the ultrasound just two days after her initial appointment and received the results from Agarwal in the clinic right after the procedure.
“I’m an impatient person, especially in this situation, so to immediately rule out a blockage in my fallopian tubes was a relief,” said Kristina, who will soon undergo fertility treatment.
Reasons for blocked fallopian tubes often include an infection, endometriosis and prior surgeries. Agarwal says there is no cookie cutter treatment plan.
“Each case is unique, and if I find a blockage in the fallopian tubes, I work with my patient to formulate an appropriate treatment plan – one that is medically sound and is also acceptable to the patient,” said Agarwal, who performs one to three of the new ultrasound tests weekly.
Some of those treatment plans for women with tubal blockage may involve taking fertility medicines, having the diseased tube removed surgically or undergoing in-vitro fertilization.
“The ultrasound was a significant part of the puzzle, and now we are trying to fill in the missing pieces,” said Kristina. “I am hopeful and not giving up on my dream to have another baby.”
Experts to provide specialized care to Team USA athletes
UC San Diego Health System has been designated an Official U.S. Olympic Regional Medical Center, joining a national network of leading medical providers selected by the United States Olympic Committee to provide comprehensive medical services to Team USA athletes, including orthopedics and sports medicine, primary care, cardiovascular care, neurosurgery, cancer care and physical therapy.
The USOC’s National Medical Network was launched in 2013. It provides medical care to athletes through partnerships with top-tier medical providers that have proven expertise in multidisciplinary sports medicine care, with an emphasis on screening, prevention and participation in research and education.
“We are honored to receive this prestigious designation by the USOC and to help athletes of all levels reach their full potential. It underscores UC San Diego Health System’s dedication and commitment to delivering world-class care by highly trained medical experts,” said Paul Viviano, CEO, UC San Diego Health System. “It is with pride that the specialized care we provide to Team USA athletes is also available to our active San Diego community.”