Cedars-Sinai • Winter 2016
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BRAIN QUAKE In This Issue 20 Unbreakable
10 One Smart Dummy
28 Path to Prevention
14 Genetic Protection From Diabetes
Today, stroke affects the old … and not so old. Risk in young people increases with obesity, sports injuries, and birth control pills — but a perplexing element of chance is involved. How physicians and patients can strike back.
Alzheimer’s disease is a dreaded diagnosis. A breakdown of what makes the condition so serious — and what the experts are doing to diminish its power with drugs, early diagnosis, and innovative clinical studies.
Anesthesiologists face life-and-death decisions daily. As residents, they must learn to manage any type of crisis. Enter robotic patient simulators that complain, experience cardiac arrest, and teach lifesaving lessons to medical teams.
A newly discovered genetic mutation could lower the risk of Type 2 diabetes, which could open new frontiers in drug development — and open the door to personalized diabetes treatment.
30 Active Duties
STROKE INCIDENCE IS RISING IN ADULTS UNDER 50. FROM PREVENTION TO RESEARCH:
HOW WE STRIKE BACK. PLUS: ALZHEIMER’S DISEASE PREVENTION P28
When Charles Trevino learned he had prostate cancer, he refused aggressive therapy. Instead, he joined a growing number of men who choose active surveillance — a highly successful, too often misunderstood, approach.
PROSTATE CANCER CAN WAIT P30
PUB_DIS (12/15)
Cedars-Sinai
BEFORE A BREAKTHROUGH STARTS IN OUR RESEARCH LABS EXECUTIVE VICE PRESIDENT AND DEAN OF MEDICAL FACULTY Shlomo Melmed, MD SENIOR VICE PRESIDENT AND CHIEF DEVELOPMENT OFFICER Arthur J. Ochoa, Esq. VICE PRESIDENT, MARKETING AND COMMUNICATIONS Rich Elbaum DIRECTOR OF CONTENT DEVELOPMENT Kelly Carolipio SENIOR EDITOR Laura Grunberger MANAGING EDITOR Susan L. Wampler ASSOCIATE EDITOR Sarah Spivack LaRosa DESIGN B&G Design Studios, www.bgdesignstudios.com
CEDARS-SINAI DISCOVERIES
© 2015 by Cedars-Sinai. All rights reserved. Reproduction or use in whole or in part without written permission is prohibited. Cedars-Sinai Discoveries is a semiannual magazine produced by Cedars-Sinai’s Community Relations and Development Department. Please email questions, comments, or requests for more information to: groupeditorial@cshs.org. MAIL:
Senior Editor Cedars-Sinai Discoveries 8700 Beverly Blvd., TSB 210 Los Angeles, CA 90048 PHONE: 323-866-6895 EMAIL: groupeditorial@cshs.org To subscribe to Discoveries magazine, visit discoveriesmagazine.org. For more information about Cedars-Sinai, visit cedars-sinai.edu. This publication is for informational purposes only and should not be relied upon as medical advice. It has not been designed to replace a physician’s medical assessment and medical judgment. Always consult first with your physician regarding anything related to your personal health.
ABOUT CEDARS-SINAI
THE MEDICAL CENTER MAINTAINS THE
Cedars-Sinai is a national leader in providing high-quality, patient-centered healthcare encompassing primary care as well as specialized medicine and conducting research that leads to lifesaving discoveries and innovations. Since its beginning in 1902, Cedars-Sinai has evolved to meet the healthcare needs of one of the most diverse regions in the nation, continually setting new standards in quality and innovation in patient care, research, teaching, and community service. Today, Cedars-Sinai is widely known for its national leadership in transforming healthcare for the benefit of patients. Cedars-Sinai impacts the future of healthcare globally by developing new approaches to treatment and educating tomorrow’s physicians and other health professionals. Cedars-Sinai demonstrates a longstanding commitment to strengthening the Los Angeles community through wide-ranging programs that improve the health of its most vulnerable residents.
FOLLOWING GOALS FOR BIOMEDICAL RESEARCH:
• Sustain a program of outstanding biomedical research, healthcare services, and nursing research by fostering basic and clinical investigation in the prevention and causes of medical illnesses, their pathologic mechanisms and diagnoses, and the development of cures for the ailments that afflict our society • Translate research discoveries appropriately to a clinical setting • Provide research training opportunities for graduate students and professional teaching programs • Foster the transition of biomedical discoveries to the realms of product development, patient care application, and marketing • Provide cross-fertilization and interdependent synergy between the medical center and the biotechnology industry • Protect the rights of human and animal subjects
Cedars-Sinai is fully accredited by the Association for the Accreditation of Human Research Protection Programs Inc. (AAHRPP) for assuring protection for our human subjects during research. Cedars-Sinai was the first institution in California to receive this designation. AAHRPP is a Washington, D.C.-based nonprofit organization that uses a voluntary, peer-driven educational model to accredit institutions engaged in research involving human subjects. Cedars-Sinai Health System does not discriminate against any person on the basis of race, color, national origin, disability, age, or sex in admission, treatment, or participation in its programs, services, and activities, or in employment. For further information about this policy, contact the vice president, Corporate Integrity Program, at 323-866-7875.
IT FIRST STARTS HERE. With hundreds of active research projects going on, it’s the everyday gift that helps fuel our most important medical advancements. Caring people, just like you, contributing to our research team in a vital way that could advance new treatments and technologies to help change lives. That’s because at Cedars-Sinai, every breakthrough begins with you. Learn more about how you can make a gift that is the start of something great, at giving.cedars–sinai.edu. MICHAEL BERNS, CEDARS-SINAI DONOR
GIVING.CEDARS-SINAI.EDU
Contents WINTER 2016
In This Issue
Max Gerber
20 Unbreakable Chelsy Colangelo was just 28 when she collapsed from a stroke. She’s not alone: Stroke incidence is up in younger adults. How we can strike back with science, awareness, and lifestyle choices.
From the Dean of Faculty
T Our most ambitious fundraising effort to date, the $600 million Campaign for Cedars-Sinai will propel groundbreaking research and patient care for decades to come.
he past 20 years have seen spectacular progress at Cedars-Sinai. Our partnership with like-minded philanthropists has enabled us to build a world-class academic enterprise dedicated to promoting health and eradicating disease. Our most ambitious fundraising effort to date, the $600 million Campaign for Cedars-Sinai will propel groundbreaking research and patient care for decades to come. Donors will have the opportunity to invest in the most relevant biomedical research areas of our time, including five strategic initiatives: disease prevention and control; precision medicine and targeted therapies; aging and longevity; innovations in healthcare and technology; and education and training. A 10 percent shortfall of physicians is predicted as soon as 2020. Cedars-Sinai is responding by training hundreds of future clinicians and investigators in dozens of accredited specialty programs, including residencies, fellowships, continuing medical education, and the Graduate Program in Biomedical Science and Translational Medicine. Philanthropic support will enable our healthcare teams to advance the field of precision health. Our experts are targeting cancer-causing gene mutations, tailoring heart disease treatment for women, and unraveling the underpinnings of many complex diseases. And, as people live longer, the campaign will also fund programs that take on diseases of aging, such as cancer, diabetes, cardiovascular disease, dementia, and osteoporosis. At Cedars-Sinai, we foster innovation in the laboratory and the clinic. One remarkable example is technology that maintains the viability of donor hearts so that transplant patients can receive organs from distant centers. At the Board of Governors Regenerative Medicine Institute, our scientists develop stem cell technologies to create powerful models that may radically change the way we understand and treat a host of ailments. Our healthcare teams have made disease control and prevention their mission. Key funding initiatives include those dedicated to interdisciplinary research and treatments in cancer, advanced heart failure, diabetes and obesity, and inflammatory bowel disease. This issue of Discoveries touches on some of these efforts with compelling stories about stroke, prostate cancer, Alzheimer’s disease, and more. Our world-class faculty and staff continue to expand the boundaries of biomedical science — and we will continue on our trajectory of discovery with the partnership of a visionary community of readers like you.
Shlomo Melmed, MD EXECUTIVE VICE PRESIDENT, ACADEMIC AFFAIRS DEAN OF THE MEDICAL FACULTY HELENE A. AND PHILIP E. HIXON DISTINGUISHED CHAIR IN INVESTIGATIVE MEDICINE
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Contents Features 28 Path to Prevention Alzheimer’s disease has earned its odious reputation. It cannot yet be cured or prevented, and the disease reaches into the brain long before symptoms appear. But investigators and physicians are attacking Alzheimer’s from every angle, pioneering tools for early detection and analyzing the disease in its preliminary stages. Piece by piece, investigators and clinicians at Cedars-Sinai are puzzling out promising solutions to this insidious condition.
30 Active Duties More and more men with prostate cancer are opting out of traditional treatments such as surgery, radiation, and hormone therapies and are choosing active surveillance. They partner with their physicians to monitor prostate tumors with cutting-edge tools to aggressively manage their own health. This is a major stride toward sophisticated, personalized healthcare that promotes value and quality of life, and the benefits of watchful waiting.
SLIDESHOW VIDEO AUDIO LEARN MORE
On the Web Explore the digital edition of Discoveries magazine for web exclusives, videos, and interactive features, including a patient’s perspective on active surveillance for prostate cancer — all available at discoveriesmagazine.org
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Departments 5 NEWS & NOTES
6 STATS
18 Q&A
Using nanoparticles and magnets to direct stem cell therapy to the site of tissue damage; how a stem cell injection may reverse vision loss caused by macular degeneration; exposing the tangled roots of amyotrophic lateral sclerosis (ALS); a new personalized approach to fighting breast and prostate cancers; cooking up cures at the new Biobank and Translational Core Facility; genetic protection from diabetes; a one-two punch to pancreatic cancer; an improved HPV vaccine; recreating brain and intestinal cells from long-deceased patients; the first study of its kind on the genetics of inflammatory bowel disease in AfricanAmericans
Women in clinical trials
How Shelly Lu, MD, overcame her initial dislike of laboratory work to build a career at the cutting edge of gastroenterology research
9 WHO’S WHO Keeping time with Eugenio Cingolani, MD, who is developing a radically different kind of pacemaker — made of a patient’s own cells
10 MY DEVICE Robotic patient simulators are helping train anesthesiologists to make smart, lifesaving decisions as they build competency in crisis management in a highly realistic, simulated environment.
37 FACULTY NEWS New PhD class in Biomedical Sciences and Translational Medicine pursues the highest calling in biomedical science — the translation of discovery to advances in care; awards, grants, and recruitment news; in memoriam
40 OPINION 17 TIME CAPSULE A look back at the dye bromsulphalein, which was used to test liver function in the early 20th century
With the proven power of vaccination to save lives, it is time for the misleading “debate” to end and for meaningful dialogue between caregivers and skeptical parents to begin.
ON THE COVER Stroke incidence is rising at an alarming rate in adults under 50. From prevention to research: how we strike back. Photo: Dom Savini
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SAVE OUR STORY Come celebrate the more than 100-year history of Cedars-Sinai by visiting the newly launched Historical Conservancy Exhibit, located adjacent to the Medical Library on the Plaza Level. You can help safeguard our proud heritage by donating your keepsake, commemorative items, or any medical treasure to the Historical Conservancy. For more information, contact Leo Gordon, MD, at historicalconservancy@cshs.org or 323-866-2925.
News & Notes Winter 2016
6 STATS | 9 WHO’S WHO | 10 MY DEVICE | 17 TIME CAPSULE | 18 Q&A
Magnet Field Although stem cells can be a potent weapon in the fight against disease, simply infusing a patient with stem cells does not guarantee that the cells will travel to the area where they are needed. Nanoparticles and magnets may help. “Infusing stem cells into arteries in order to regenerate injured heart muscle can be inefficient,” says Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute, who led the research team. “Because the heart is continuously pumping, the stem cells can be pushed out of the heart chamber before they even get a chance to start healing the injury.” Photograph by CLINT BLOWERS
In an attempt to direct beneficial stem cells to the site of the damage, investigators coated iron nanoparticles with two kinds of proteins that recognize and bind specifically to stem cells and to injured cells in the body. After the nanoparticles were infused into the bloodstream, they successfully migrated to the appropriate area and initiated healing. Targeting was further enhanced by placing a magnet above the injured heart. “Through magnetic resonance imaging, we were able to see the iron-tagged cells traveling to the site of injury, where the healing could begin,” says Marbán. WINTER 2016 | DISCOVERIES |
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Stem Cell Injection May Reverse Vision Loss
STATS : WOMEN IN CLINICAL TRIALS
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percentage of female participants in heartrelated studies (reported in 2014), even though heart disease is the leading cause of death for women in the U.S.
6
THREE
the number of representatives in Congress currently co-sponsoring the Research for All Act. If it becomes law, it will increase the study and analysis of sex differences in biomedical research.
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In this study, iPSCs were programmed to become neural progenitor cells, or iNPCs, cells that can self-renew and differentiate into the major cell types of the central nervous system. When iNPCs were injected into animal models, grafted cells began to migrate to form a protective layer, which prevented further degeneration of the retinal cells necessary for vision. The stem cell injection resulted in 130 days of preserved vision in animals, translating to roughly 16 years in humans. “This is the first study to show preservation of vision after a single injection of iNPCs into an animal model for retinal degeneration,” says Shaomei Wang, MD, PhD, lead author of the study — which was published in the journal STEM CELLS — and a research scientist in the Eye Program at the Regenerative Medicine Institute. Investigators are continuing animal studies to test the safety and longterm efficacy of the stem cell treatment. Hopefully, these cells will provide a valuable source for treating retinal degeneration in clinical applications.
1977 50 year the Food and Drug Administration (FDA), concerned about the possible effects of experimental drugs on fetuses, banned all women of childbearing age from participating in clinical trials — including lesbians, women using birth control, and abstinent women. The ban lasted until 1993.
percentage of randomized clinical trials studying depression in 2007 that did not analyze outcomes by gender, even though U.S. women are twice as likely as men to have the condition.
Paul Garland
An injection of stem cells into the eye may slow or reverse the effects of early-stage, age-related macular degeneration, according to new research from scientists at Cedars-Sinai. Investigators suspect that age-related macular degeneration is caused by genetic and environmental factors, and no current treatment slows the progression of the disease. It occurs with deterioration of the macula, the small portion of the retina at the back of the eye that contains light-sensing neurons. This deterioration causes blind spots in the central field of vision. The disease affects nearly 15 million Americans and is the leading cause of vision loss in people over 65. With support from the David and Janet Polak Foundation Stem Cell Core Laboratory at the Board of Governors Regenerative Medicine Institute, scientists in the Induced Pluripotent Stem Cell (iPSC) Core reprogrammed adult human skin cells into an embryonic stem-cell-like state through complex genetic manipulations that forced the cells to “go back in time.” The process essentially turns the cells into blank slates that can be grown into a wide variety of cells — nervous system, blood, bone, or heart, for example.
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Points of Origin Three recent discoveries exposed a few of the tangled roots of amyotrophic lateral sclerosis (ALS), a disease that attacks motor neurons — nerve cells responsible for muscle function — in the brain, brainstem, and spinal cord. The disease causes progressive weakness and muscle failure throughout the body, with patients typically surviving only three to five years after diagnosis.
1. Genes Genetics may play a larger role in ALS than previously thought, potentially accounting for more than one-third of all cases. “This sheds new light on ALS’ origins, especially in the 90 percent of patients with no family history of the disease,” says Robert Baloh, MD, PhD, director of Neuromuscular Medicine and the ALS program in CedarsSinai’s Department of Neurology, the Ben Winters Chair in Regenerative Medicine, and the study’s senior author. Researchers identified several new or rare
ALS mutations and found that patients with defects in multiple ALS-associated genes experience onset about 10 years earlier than patients with single-gene mutations. This discovery anticipates a personalized approach that could potentially deliver gene-specific therapies to correct ALS defects.
2. Aging Neurons benefit from astrocytes, which are supportive cells that feed and maintain the neurons. New research at Cedars-Sinai demonstrates that ALS worsens
13 80 percentage of the National Institutes of Health (NIH) budget used to fund research on women’s health issues.
percentage of FDAapproved prescription drugs removed from the market between 1997 and 2001 because of their health risks to women.
as these helper cells age. Prior investigations showed that astrocytes failed to support motor neurons in animal models with ALS. This study, spearheaded by then-graduate student Melanie Das, PhD, discovered that even normal aging reduces functionality. “Aging astrocytes lose their ability to support motor neurons in general, and they clearly fail to help those attacked by ALS,” says Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute, the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine, and lead
246 million
dollars the NIH spent on women’s heart disease research in 2014. In comparison, $959 million was spent on women’s cancer research out of a total NIH budget of $30 billion.
investigator. The researchers are now evaluating the potential cellular antiaging properties of a specially engineered protein.
3. The Brain Dr. Svendsen led another study exposing the brain’s significant role in ALS progression, a process previously thought to originate in the muscles or spinal cord. Communication breakdowns at neuromuscular junctions — where nerve fibers connect to muscle fibers — lead to muscle failure.
Because the earliest and most obvious damage is seen at these junctions and in the spinal motor neurons, most ALS research has focused on these areas. Dr. Svendsen’s team, steered by postdoctoral scientist Gretchen Miller, PhD, looked higher up in the system, suppressing the ALS mutation in animal brains. They found that onset of the disease was delayed, spinal motor neuron survival improved, neuromuscular junction health was extended, and the animals lived longer.
LEARN MORE Find out more about aging and longevity and the Campaign for Cedars-Sinai at giving.cedars-sinai.edu
FIFTY
percentage increase in enrollments in the Gilda Radner Hereditary Cancer Program in 2014, spurred by Research for HerTM, Cedars-Sinai’s groundbreaking online registry that matches women with research studies and clinical trials. The program consists of several research studies for women at elevated risk for breast and ovarian cancer, and is part of the Women’s Cancer Program at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute.
Sources: Library of Congress, Government Accountability Office, Food and Drug Administration, National Institutes of Health, and Women’s Health Alliance
WINTER 2016 | DISCOVERIES |
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HELP BY VISITING A DIFFERENT KIND OF BANK. Make a different kind of donation by giving blood. All it takes is one hour to save up to two lives. Schedule an appointment now at donatebloodcedars.org or call 310-423-5346.
Š 2015 Cedars-Sinai
WHO’S WHO
The Timekeeper
A NATURAL METRONOME
NAME:
Eugenio Cingolani, MD Director, Cardiogenetics-Familial Arrhythmia Clinic, Clinical Cardiac Electrophysiology Section, Cedars-Sinai Heart Institute
[
]
SETTING THE PACE A healthy heart contains a natural pacemaker: the sinus node. Dr. Cingolani’s team is recreating this specialized cluster of cells in animal models. “What we did was inject a single gene that reprogrammed normal heart cells into functioning pacemaker cells,” he says. The animals receiving the gene showed faster heartbeats than those that did not — and the improvement lasted for the duration of the 14-day study.
COUNT OFF
DRUM HEAD
Dr. Cingolani arrived at Cedars-Sinai as a cardiology fellow in 2008 and scored a Sports Spectacular fellowship in 2010.
Dr. Cingolani is enamored of rhythm in all its forms and has played the drums since he was 10.
DRUM FILL
CHANGING TEMPO
“Electrophysiology interests me because it describes complex mechanisms that lead the heart to beat for life. I’m always looking for gaps between our knowledge and patient treatment.”
STACCATO
THE BRIDGE Pacemaker infections, while not common, are serious and require removal of the device. The biological pacemaker could act as a bridge. Plus, performing multiple procedures increases the risk of complications, especially for pediatric patients. “Children grow, but pacemakers don’t stretch. For our youngest patients, the potential of biological pacemakers is fantastic.”
To decompress, he heads out to sea in his Star-class racing boat in Santa Monica Bay. He sailed competitively in his home country of Argentina.
When it comes to implantable devices, miniature is best. One pacemaker under study is the size of a large pill, but nothing else in development may be quite as tiny as a single gene!
CUED UP Dr. Cingolani and his colleagues' follow-up studies already are showing promising results. “We have seen that the biological pacemaker can prolong results beyond two weeks, and we have also shown that the animals have a very good response.” He hopes to initiate human clinical trials with the biological pacemaker within two years.
Misha Gravenor
Heart rhythm disorders and electrophysiology expert; drummer (not expert)
More than 150,000 Americans each year have an electronic pacemaker implanted to help their hearts beat normally. Eugenio Cingolani, MD, is developing a radically different kind of pacemaker — one made of a patient’s own cells.
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N & N MY DEVICE
One Smart Dummy THE PROBLEM The job of an anesthesiologist might seem simple: Put the patient to sleep; keep the patient asleep; wake the patient up. But an anesthesiologist’s job is a vital and delicate balancing act that includes managing critical life functions and coordinating with a surgical team. “Thousands of disease states make the anesthesia of one patient different from another,” says Roya Yumul, MD, PhD, director of Simulation for Anesthesiology at Cedars-Sinai. “A person might have a difficult airway or be on a prescription drug. Each patient requires a different combination of medications, maintenance, and monitoring.” Some 70 percent of all errors in medicine are attributable to human factors. The key to protecting patients is to expect the unexpected, which is a challenge for young doctors who haven’t faced many unusual or complex clinical scenarios. “You can’t possibly capture all the critical things that can happen in an operating room in just four years of residency training,” notes Dr. Yumul. The first stage of training happens in the classroom with the use of a dummy head, or a head with a thorax, but Dr. Yumul says that is not enough.
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“Even though trainees read about a task or crisis management and understand the problem intellectually, they haven’t experienced the stress of working in a real clinical scenario and the stress of working with a team.”
THE SOLUTION The only way to experience the kind of immersion Dr. Yumul describes is, well, to experience it. That happens in the Women’s Guild Simulation Center for Advanced Clinical Skills at CedarsSinai, where anesthesiology residents and fellows train in fully equipped procedure rooms with real surgical teams. Substituting for living patients are robotic, life-size mannequins
Rachael Porter
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that breathe, talk, vomit, bleed, and exhibit vital signs. Dr. Yumul has created more than 50 life-or-death clinical scenarios with these patient simulators. “These are things that do not occur often, but if they do happen and you’re not trained, it’s going to be a disaster,” she says. “It’s going to be mortal.” The scenes include complications such as malignant hyperthermia — a rare and life-threatening reaction to anesthesia — or a patient having a heart attack or stroke. Using the labor-anddelivery mother and infant simulators, a trainee might face an amniotic fluid embolism. “The potential problems don’t always originate with the patient,” Dr. Yumul adds. “Equipment can fail, like an oxygen pipeline malfunction. You need to know how to handle these scenarios.” In essence, what she teaches is competency in crisis manage-
ment. Her trainees learn teamwork and communication along with clinical skills and management in a highly realistic environment. “We debrief with the residents at the end of the simulation session and their feedback typically is: ‘At some point I forgot I was in a simulation. I wanted to save the patient.’ The mannequin makes it real,” Dr. Yumul says. The simulation center is used by nearly every discipline in the hospital and by a wide range of caregivers, from nurses in training to seasoned surgeons practicing new techniques. Anesthesiology, however, is credited with pioneering modern simulation techniques. “Our discipline copied aviation simulation techniques because our work is similar to that of pilots,” she explains. “We have a takeoff, a plateau, and a landing: We render the patient unconscious, we maintain them for the course of the surgery, and we make sure they wake up pain free, with stable blood pressure.” With the help of a few cooperative patient simulators like Hal, pictured here, many safe landings lie ahead. Dr. Yumul is program director for Residency Education, Core Program director and director of Simulation for Anesthesiology, and co-director of Simulation at Cedars-Sinai.
LEARN MORE
Find out more about education and training and the Campaign for Cedars-Sinai at giving.cedars-sinai.edu
WINTER 2016 | DISCOVERIES |
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How I got through 15 months without a heart. I had advanced heart failure; I needed a transplant immediately. So the team at Cedars-Sinai gave me a portable, artificial heart that kept me alive until they could find a donor. For 15 months I literally walked around without a heart in my body. It was a tough time, so I created music playlists to keep me going. I gave them names like Gospel Old School, Jazztacy and Chili Smooth. This past year I received a human heart. Now I’m working on the playlist for my comeback. 1-800-CEDARS-1 | cedars-sinai.edu/heartstories
Larry Lewis Playlist Enthusiast
Š 2015 Cedars-Sinai
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Cancer’s Weak Spot Cedars-Sinai scientists have identified a gene responsible for the growth of many breast and prostate cancers. The presence of this gene can help identify patients who might respond well to certain chemotherapy drugs. “Understanding biomarkers like this gene is a vital step toward improving cancer research and care,” says Michael Freeman, PhD, vice chair of Research in the Department of Surgery and lead author of the study. “New profiling strategies can improve our ability to treat cancer patients.” The newly identified biomarker — a gene called DIAPH3 — helps make cells rigid. The study found that when the gene is absent, cells become softer and can squeeze through tissue spaces, catalyzing disease growth. The good news is that these shapeshifting cells are vulnerable to cancer-fighting drugs called taxanes, which attack the most aggressive forms of the disease. Next steps involve developing a tool that will allow researchers to test for the gene in patients.
Cooking Up Cures Cedars-Sinai’s new Biobank and Translational Core facility can store millions of tissue and blood samples for analysis using highly advanced technology. While these biospecimens might be less appetizing than items found in a home or restaurant kitchen, they will prove critical to future generations of patients. Here’s a handy conversion chart to help measure the differences and similarities.
BIOBANK
KITCHEN
MISSION
To serve science and the community
To serve hungry guests
SIZE
Nearly 7,000 square feet
An average of 225 square feet in homes and 1,050 square feet in restaurants
ORGANIZATION
Three units: one for collecting and preserving biospecimens, one for research pathology, and one for digital image analysis
It’s essential in a kitchen. Just ask Martha Stewart.
PREP
Tissues are prepared for analysis in the histology lab.
Chop, julienne, slice. Repeat.
TECHNOLOGY
Software tracks the precise location of each of the 45,000 biospecimens collected from 3,000 patients — and those numbers continue to grow.
Smart refrigerators track your shopping list.
COOLNESS FACTOR
Thirty liquid nitrogen tanks chilled to minus 180 degrees Celsius and 20 compressor-powered freezers that can reach minus 80 degrees Celsius
Refrigerators should be set to about 4 degrees Celsius and freezers to 0.
VOLUME
Each liquid nitrogen container holds up to 38,000 blood and tissue samples in nitrogen vapor. Each freezer can hold 100,000 samples.
Standard home refrigerators hold between 14 and 30 cubic feet of food, beverages, and whatever that brown thing in the back used to be.
PROTEIN
Investigators analyze proteins and other biochemical substances that indicate disease or provide new targets for therapies.
Meat, fish, or vegetable sources are essential to a healthy diet.
DIGITAL OUTPUT
Vivid digital images from tissues are converted into numbers. Pattern recognition software searches for signs of disease in the images.
EXPIRATION DATE
Living cells are maintained for several years in liquid nitrogen containers. Other samples can be kept indefinitely.
Are you sure you want to drink that milk?
OPEN FOR BUSINESS
All Cedars-Sinai investigators can obtain tissue samples or have slides prepared from samples they gather.
Restaurants welcome all, according to dress code. Homes may be more discerning.
CLEANLINESS
Living cells are handled in a sterile area to keep them free from contamination.
You might want to start with disinfecting that counter where the cat was sitting.
PROFIT
Cedars-Sinai’s Biobank is nonprofit, benefiting patients and medical research.
The personal fulfillment of a well-prepared meal
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Genetic Protection From Diabetes
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search,” says Richard Bergman, PhD, director of the Cedars-Sinai Diabetes and Obesity Research Institute and the Alfred Jay Firestein Chair in Diabetes Research.
“Now we need to better understand why and how this genetic mutation might protect people from developing diabetes.”
David Plunkert
An international team of scientists led by a Cedars-Sinai investigator has identified a genetic mutation that appears to protect people from developing Type 2 diabetes. Investigators from the U.S., Asia, and Europe analyzed the genes of 81,000 people who did not have Type 2 diabetes and compared their genetic information to that of 16,000 diabetics. They found that having a genetic mutation in one particular gene — GLP1R — appeared to lower a person’s risk of developing Type 2 diabetes by 14 percent. Mark O. Goodarzi, MD, PhD, director of the Division of Endocrinology, Diabetes and Metabolism at CedarsSinai, who led with the study, was encouraged by the discovery’s potential to lead to new treatments. “The identification of genes that influence the risk of diabetes is going to open new frontiers in diabetes drug development. We now have a wonderful opportunity to personalize treatment and prevention of this chronic disease.” Type 2 diabetes affects the production of insulin — a vital sugar-regulating hormone — and its ability to control metabolism. In diabetics, the body’s failure to manage blood sugar can lead to heart attacks and other serious health problems. According to the Centers for Disease Control and Prevention, more than 29 million Americans have Type 2 diabetes. Current treatment involves a combination of insulin and oral medication, or bariatric surgery. “This newly identified mutation in such a large study group is a critical discovery in the field of diabetic re-
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A One-Two Punch to Pancreatic Cancer A clinical trial is underway at CedarsSinai to fight one of the deadliest types of cancer: locally advanced pancreatic cancer, which has an abysmally low five-year survival rate of just 6 percent. To move the needle toward longer survival and better outcomes, radiation oncologist Richard Tuli, MD, PhD, in the Cedars-Sinai Department of Radiation Oncology at the Samuel Oschin Comprehensive Cancer Institute created a novel multi-step therapy. An animal study combined radiation therapy with a drug that inhibits repair of cancer cells. Chemotherapy and radiation shrink tumors by damaging their DNA, but pancreatic cancer cells tend to recover and proliferate. When the drug was included with radiation, survival was prolonged. These findings led to a clinical trial in which participants receive chemotherapy and radiation in addition to the study drug, which investigators hope will provide a synergistic benefit.
A Better HPV Vaccine Three vaccines have been approved for human papillomavirus (HPV) — but the newest one may be the best for protecting against HPV-related cancers. The vaccine, 9-Valent, could prevent 80 percent of cervical cancers in the United States if given to all children before they are exposed to the virus. Doctors recommend patients receive the vaccine at 11 or 12 years of age. The vaccine has the potential to protect
against approximately 19,000 cancers, including anal, penile, and mouth and throat cancers, and represents an 11 percent increase in cancer protection compared to the effectiveness of the first HPV vaccines on the market. These findings are derived from a seven-center study initiated by the Centers for Disease Control and Prevention, in conjunction with Cedars-Sinai. WINTER 2016 | DISCOVERIES |
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N&N Stem Cells Reborn
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The Pathway Less Studied Researchers have conducted an in-depth evaluation of the genetics of inflammatory bowel disease (IBD) in African-Americans — the first study of its kind, as most research on IBD has been conducted on Caucasian and Asian populations. IBD has also historically been underdiagnosed among AfricanAmericans, though more and more cases are now reported every year. Evaluating more than 1,500 African-American patients, the study found that they shared several genetic risk factors for IBD with whites and Asians. People with IBD experience chronic and often debilitating inflammation of the digestive tract. These diseases, which include ulcerative colitis and Crohn’s disease, are lifelong and can cause severe diarrhea, pain, fatigue, anemia, weight loss, and an increased risk of cancer. “The hope is that genetic advances in IBD will allow us to develop new therapies and more personalized approaches to managing these chronic diseases,” says Dermot McGovern, MD, PhD, director of Translational Medicine at the CedarsSinai F. Widjaja Foundation Inflammatory Bowel
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and Immunobiology Research Institute, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics, and a co-senior author on the study. “This research is important because it extends these possible advances to the African-American population, who may be at risk of more severe IBD.” Dr. McGovern, with colleagues at Johns Hopkins University School of Medicine and Emory University, looked for new regions of the genome that might raise IBD risk in African-Americans. They found strong evidence for previously unidentified variations in one major IBD gene. Analyses performed at Cedars-Sinai investigated cellular pathways — complex systems of internal communication — that result in IBD development. A number of pathways were similar to those seen in white patients. However, a few appear to be unique to African-Americans — which could lead to more personalized approaches to managing and preventing disease. In addition to three senior authors, the study was authored by 52 investigators in the United States and Canada.
Davide Bonazzi
Investigators have developed a method to recreate brain and intestinal cells from patients who died decades ago. Using stored blood samples, these scientists are breaking new ground in the study of debilitating illnesses such as spinal muscular atrophy and inflammatory bowel disease. “The potential implications of this research are vast,” says Dhruv Sareen, PhD, the study’s lead author and director of the David and Janet Polak Foundation Stem Cell Core Laboratory in the Board of Governors Regenerative Medicine Institute at CedarsSinai. Using long-ago donated blood, he and his colleagues developed blank-slate stem cells in a petri dish. The process essentially reanimates the diseased cells. These were developed into functional motor neurons and threedimensional intestine replicas called organoids. This allowed the investigators to connect the scattered dots between a deceased patient’s symptoms, genetic information, and the behavior of the affected brain and gut cells. Their research could yield new therapies for people who suffer from aggressive conditions that proved fatal to the deceased patients.
TIME CAPSULE
N&N
Hold the Onions In the early 20th century, the dye bromsulphalein was used to test liver function. A patient would be injected with the dye and then, about 30 minutes later, blood was drawn and put into a centrifuge to separate out a clear serum. The serum was mixed with a chemical solution to bring out the color of the dye, which was
compared to a set of color standards like the one pictured. Liver function is still measured with a blood test today, but the process is far more sophisticated. Lab technicians can now determine the levels of key proteins and enzymes that tell a detailed story about liver activity. The Bromsulphalein Colorimeter set of color standards is maintained by Cedars-Sinai’s Historical Conservancy, along with a wondrous assortment of donated artifacts and documents related to medicine and the development of the hospital since the early 1900s.
Rachael Porter
Bromsulphalein Colorimeter Manufactured by Hynson, Westcott & Dunning Inc., Baltimore, MD Date of manufacture: circa 1910–1920
VIDEO
Find out more about Cedars-Sinai’s Historical Conservancy at discoveriesmagazine.org
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Q A &
Life & Science: Shelly Lu, MD By Sarah Spivack LaRosa
Dr. Shelly Lu is back. She first arrived at Cedars-Sinai as a resident in internal medicine. Twenty-five years later, she has earned a distinguished position in her field, attracted the acclaim of her peers, and built a life philosophy that she is putting to work as the new director of Cedars-Sinai’s Division of Gastroenterology.
Q. Did you always want a career in medicine? A: I’m Chinese and grew up in Taiwan. My mother wanted me to pursue
medicine, but, as a rebellious kid, I said no. My father is a poet, and I love music and literature. But when I attended UCLA, my English was horrible. I majored in biology instead, and then I went into medicine because it gave me the most choices. That’s my philosophy: Don’t close any doors. Q. What drew you to research? A: The first six months I spent in a lab, I absolutely hated it. Basic lab work is
grueling — most of the time, the findings are not positive. But after learning to adapt to that pace, I started to get interesting findings. You get to play Sherlock Holmes, work on the cutting edge, and solve problems to discover the inner workings of disease.
SHELLY LU, MD EXPERTISE
Gastroenterology and liver diseases
Diseases, Keck School of Medicine, USC DAUGHTERS
John Livzey
MENTOR
Neil Kaplowitz, MD, chief, Division of Gastroenterology and Liver
Two. They are passionate about the arts and are planning careers in medicine.
HUSBAND
GRANTED
Lawrence Maldonado, MD, faculty in Internal Medicine, Cedars-Sinai; art buff
Five active National Institutes of Health–funded Research Project Grants, or R01s. Most investigators are thrilled to win one R01, never mind five.
EXTRA CREDITS
Poised to become senior associate editor at Gastroenterology, the field’s leading journal
Q. What is most exciting about leading this division? A: When I accepted this position, Cedars-Sinai
didn’t have its own gastrointestinal fellowship program — it was in partnership with UCLA. Creating a fellowship program was my No. 1 priority, and we’ve done it! Our first three fellows started this summer. We will become an academic powerhouse to match our clinical expertise: I’d like to see us in the top five in the nation in a few years. I’m impatient to see it happen! Q. Can many of your research projects lead to clinical applications and treatments? A: Absolutely. Fatty liver, for instance, is the major
cause of liver disease globally. More than 60 percent of U.S. adults are overweight, and the majority of those have fatty liver. The condition can progress to a more severe form associated with fibrosis, cirrhosis, and even liver cancer. We recently recruited Mazen Noureddin, MD, to start a fatty liver research program. We are working to discover the basic mechanisms of nonalcoholic fatty liver to develop biomarkers to identify patients with the more severe form of the disease and to personalize treatment. Cedars-Sinai has fantastic scientists for me to collaborate with. We are looking at SAMe, which is widely available as a dietary supplement. It’s also made naturally in the body. Research in animals has shown that SAMe may be effective in preventing liver and colon cancer. We’re going to look at a group of patients who have a gene mutation that puts them at very high risk of colon cancer to see if SAMe can reduce cancer development. If so, it will be a wonderful achievement! Q. You seem very positive and self-motivated. What’s your philosophy? A: If my gut tells me it will be okay, I go with the
flow. I’m at an age and a stage in my career when it’s time to take up new challenges. Life is short, so you do the best you can — and whatever you achieve, it’s good enough. Hopefully, that life philosophy is rubbing off on my kids.
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Unbreakable Chelsy Colangelo knows her brain is dying. “I’ve had a stroke! You have to help me!” But the plea collapses before reaching her lips. Instead, Chelsy’s frantic thoughts spin circles in a smoldering maze of circuits in her brain — only to crash, crumble, or vaporize in the glare of emergency room lights. Her brain is dying, and no one knows but her. By KEVIN MCCLANAHAN Photography by MAX GERBER
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Chelsy Colangelo, 29, had worked a shift behind the bar at her neighborhood Marie Callender’s the night she was blindsided by a stroke.
The doctor in the small community hospital thinks she may be drunk, or perhaps drugged. Otherwise why would a seemingly healthy 28-year-old woman collapse in a bar at 11:30 at night? Tests. Wait. Exams. Wait. Lab work. Wait for results. Chelsy spots a clock on the emergency room wall, where harrowing seconds and then minutes tick away, casually, methodically, defiantly. Terrified that the window of time to save her brain is closing, still unable to form words, she repeatedly points to the clock.
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Now 29, Chelsy is 40 years younger than the average stroke sufferer’s age. But today strokes are occurring earlier in life than ever before. According to a 2012 Neurology article, the average age of stroke onset was 71.2 in 1994, but 69.2 by 2005. The study also found that 19 percent of all strokes — nearly one in five — occur in people younger than 55. That’s a 6 percent increase over the study’s 11-year span. “We have to stop thinking of stroke as a disease of only the elderly,” says Patrick Lyden, MD, chair of the Department of Neurology, director of the Stroke Program, and the Carmen and Louis Warschaw Chair in Neurology. “Stroke is still more common among older people, but the greatest increase has occurred in the middle-aged and pre-retirement group. A stroke can happen at any age.” Dr. Lyden calls the increase alarming because stroke is the No. 1 cause of adult disability. According to a 2014 article in the journal Stroke, 32 percent of young stroke patients — those 18 to 50 — need long-term assistance with daily activities or even lose the ability to live independently. “Strokes in younger people, who are in the prime of their productive and wage-earning years, put enormous strains on families and society in a one-two punch: Just at the time patients lose their ability to make a living — temporarily or permanently — they are hit with the costs of acute treatment, rehabilitation, and, often, long-term care.” The trend is alarming but not entirely surprising, according to Dr. Lyden and Laurie Paletz, board-certified registered nurse, public health nurse, and coordinator of the Stroke Program at Cedars-Sinai (see sidebar on causes and prevention). The same major risk factors that lead to strokes in the elderly — such as diabetes, obesity, high cholesterol, high blood pressure, and smoking — increase risk at any age. Many young people were introduced to a steady stream of high-calorie, high-sugar, lownutrient fast foods at an early age, giving them a head start on stroke-producing habits. “We’re seeing 24-year-olds with high cholesterol levels because they’ve been eating fast food for years,” says Paletz, who often presents stroke awareness information at health fairs and community
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“We tell our doctors to be on the lookout for stroke in young people because it often isn’t the first thing people consider.” — Shlee Song, MD
events. “We have to get the message out to young people that strokes do happen, and choices they make can affect their risk.” To the traditional risk factors, add a few that affect younger generations in particular, such as hormone fluctuations from birth control pills or pregnancy, undetected heart defects, drug abuse, and brain artery injuries called dissections. Some risks are well-documented. Others — including migraine headaches, the use of some over-the-counter dietary supplements, and the consumption of sodas and even diet sodas — are increasingly seen by stroke experts in clinics, Dr. Lyden says, although solid scientific evidence is only now taking shape and more research is needed. “It is important to note that not every stroke is preventable or caused by poor health habits,” he adds. “Chelsy was fit and athletic, but she had a stroke anyway.”
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Chelsy learned the symptoms of stroke while earning her bachelor’s degree in sports medicine at California State University, Fullerton, where she also received a bachelor’s degree in radio, television, and film. She graduated in 2012 but continues working as a bartender at her neighborhood Marie Callender’s. She loves the job, the pay is good, and she has a group of loyal customers who can’t mistake the hearty laugh and goodnatured energy that is delivered with their drinks. She is outgoing and active, a Boston Red Sox and New England Patriots fan who played competitive softball in her adolescent years. Chelsy had worked a shift at the restaurant that night in December 2014 before meeting a few friends at a bar for a drink. After sipping a beer, she excused herself to go to the restroom. “My brain got fuzzy and I couldn’t open the stall door,” she recalls. “I couldn’t move my left hand. I thought: ‘What the heck is going on?’ It was really scary. I slid under the door, went out to my friends, and paid my tab. But when I tried to sit on the
chair, I collapsed.” Paramedics arrived quickly after the 911 call, but they took Chelsy to the closest hospital instead of one that specializes in stroke care. “It’s a tough job for an emergency room doctor because they have to be a jack-of-all-trades, thinking of all the common ailments from gastrointestinal issues to heart attacks, strokes, toxicities, and drugs. A 28-yearold usually does not present with a stroke, so it probably didn’t even hit the community hospital’s radar,” says Shlee Song, MD, associate director of the Cedars-Sinai Stroke Program and director of the Vascular Neurology Fellowship, which trains the next generation of stroke experts. “We tell our doctors to be on the lookout for stroke in young people because it often isn’t the first thing people consider.” In a study published in the Journal of Stroke & Cerebrovascular Diseases, investigators at Wayne State University/Detroit Medical Center found that eight of 57 stroke patients between 16 and 50 years of age were initially misdiagnosed. All eight were evaluated at hospitals that were not certified Primary Stroke Centers, and seven were actually discharged from the emergency department before the correct diagnosis was made. “Our study demonstrates the increasing need for ‘young stroke awareness’ among emergency department personnel,” the authors wrote. “Initial misdiagnosis can potentially lead to a lost opportunity for thrombolysis — administration of a drug that dissolves clots — in otherwise good candidates.” It also demonstrates the need for more research. One promising study shows that when the clot-busting drug called tissue plasminogen activator, or tPA, is given within about three hours of the start of an ischemic stroke — by far the most common type, caused by narrowing or blockage of an artery — the stroke’s effects may be completely reversed. In fact, giving tPA increases the number of strokes cured by 11 percent, according to Dr. Lyden, who was a key contributor to the pivotal clinical
Cedars-Sinai’s stroke team was able to save Chelsy from grave disability. Although she is frustrated at the halting pace of recovery, she has returned to the job she loves, where she can work on improving her speech and movement.
trial that led to Food and Drug Administration (FDA) approval of the drug in 1996. But stroke treatments — with tPA or new devices that in some cases can be threaded through blood vessels to grab and remove a clot — only work if they are started before too much irreversible damage is done. In her community education programs, Paletz urges people to learn the symptoms of stroke and realize that “time is brain,” and time lost is brain lost. A friend and colleague of Dr. Lyden’s — Jeffrey Saver, MD, director of the Stroke Program at UCLA — published results of a systematic literature review in the journal Stroke in 2006: “The typical patient loses 1.9 million neurons each minute in which stroke is untreated,” he wrote. WINTER 2016 | DISCOVERIES |
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Chelsy had been staring at the emergency room clock for an hour when her mom, Kathy, arrived. “I took one look at her and said to the doctor, ‘She’s had a stroke,’ and he said, ‘No, no. I don’t think so.’” I called her father and said, ‘Get down here. This is serious,’” Kathy recalls. Precious hours crept by. The doctor came and went. Nurses shuffled in and out. Exams were done. Tests were ordered. Blood was drawn. Still no answers. In the early morning hours, results of a CT head scan looked abnormal, and a follow-up CT with contrast — which provides greater detail — was later performed. The first piece of Chelsy’s puzzle finally started to come into focus: Blood and oxygen were choked off from a large area on the right side of her brain. As dawn began to break, the emergency staff scrambled to make plans to transfer Chelsy to Cedars-Sinai, a Comprehensive Stroke Center with advanced technology and experts available around the clock every day of the year. Chelsy’s father, Tom, went with her in the ambulance, and a large stroke team, led by Dr. Song, met them at the Neuroscience Intensive Care Unit at 8:27 a.m. — nine hours
“We know the brain can create new connections, and this is especially true in young people. Sometimes we see amazing recoveries.” — Michael Alexander, MD
after her collapse and well beyond the traditional treatment window. But neurosurgeon Michael Alexander, MD — professor and vice-chair of the Neurosurgery Department, and director of the Neurovascular Center — wasn’t ready to give up. An expert in the use of innovative instruments guided through blood vessels to the brain, Dr. Alexander currently leads a large clinical trial studying an angioplasty balloon and stent system that opens plaque-narrowed brain arteries. Interventions in the brain are trickier than similar treatments for clogged heart arteries because
THE AVERAGE STROKE LASTS 10 HOURS
25%
increased incidence of stroke in those aged 20 to 64 between 1990 and 2010 worldwide
1.9 80% 14 7.5 10% of strokes can be prevented
EVERY HOUR WITHOUT TREATMENT, THE BRAIN AGES EFFECTIVELY BY 3.6 YEARS
90%
of strokes are ischemic, caused by a narrowing or blockage of blood vessels in the brain
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Every minute a typical stroke goes untreated, a person loses:
of strokes are hemorrhagic, caused by bleeding in the brain
million neurons billion synapses miles of myelinated fibers
the less muscular, more delicate arteries of the brain are especially vulnerable to nicks and tears. Beginning at 9 a.m., he used 3-D angiographic imaging to confirm the presence of a clot in the territory fed by the right middle cerebral artery. He maneuvered a state-of-the-art “thrombectomy” device through vessels to grab the clot and take it out, and blood flow was fully restored by 10:15 a.m. “At first, Chelsy literally could not speak,” Kathy recalls. “She couldn’t write the alphabet. Zilch. But by the very next day, she could write the alphabet with only three mistakes — that’s how quickly she was making progress. We used pictures to figure out what she was communicating because her words would come out randomly. She couldn’t speak on command.” After three days in the Neuroscience Intensive Care Unit, Chelsy transferred to the Stroke Recovery Unit, but only for the weekend. She started inpatient rehabilitation Monday morning and went home 12 days later to continue outpatient physical, speech, and occupational therapies. Kathy estimates her vocabulary consisted of about 20 words. The first word she spoke: “mom.” Three months later, Chelsy was back at work.
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When a patient like Chelsy arrives at Cedars-Sinai, the code brain team’s first priority is confirming the diagnosis and taking action to quickly open the vessel. When the immediate crisis is resolved, neurologists and other experts search for causes or contributing factors to help prevent a recurrence. During the intensive exams Chelsy underwent following her stroke, doctors discovered a congenital heart defect. In March, she returned to Cedars-Sinai, where cardiologist Saibal Kar, MD, director of Cardiovascular Intervention Research, performed a minimally invasive procedure to repair it. “We don’t know for certain where Chelsy’s clot came from or how it ended up in the artery in her brain, but a hole between the two upper chambers of her heart — an atrial septal defect — is one possibility where a clot could have passed through to get to the brain,” Dr. Song says. Normally, oxygen-depleted blood from the veins flows into the right atrium and goes out to the lungs. The left atrium then pumps oxygen-rich blood to the body. But if a hole exists between the chambers, a clot that comes in with the venous blood flow can enter the left atrium and quickly be pumped to the brain. A similar heart defect that increases the risk of stroke is called a patent foramen ovale (PFO). A small hole that allows blood to flow between the atria in the fetus should close at birth, but in about 25 percent of people, the flap fails to seal properly. This defect usually causes no symptoms or consequences, but the gap can allow an otherwise harmless clot to be pumped to a brain artery. PFOs are found in about 40 percent of patients who have
strokes of unknown cause, and although PFO-related strokes can occur in the older population, they are more commonly seen among younger patients. Chelsy had several other risk factors, including using birthcontrol pills and having a job that required standing for long periods of time. Birth-control pills alter hormone levels and increase clotting risk. Long stretches of sitting or standing in place can contribute to formation of clots in deep veins, usually in the legs. This type of clot, called a deep vein thrombosis, or DVT, is more common in older people, but the young are not immune. Dr. Song theorizes that the combination of these two could create “the perfect storm” to bring on the stroke. Yet another scenario — the likeliest one, in Dr. Alexander’s view — holds that Chelsy had a spontaneous tear, or dissection, in her brain artery that December night. Arterial walls consist of three layers — inner, middle, and outer. If the inner layer tears and separates, the damaged tissue can obstruct blood flow. But even if the artery stays open, the body tries to heal the injury by initiating a cascade of events that leads to clotting. “Where there is a dissection, there is clotting, and the end result is often a stroke,” Dr. Song says. On the other hand, she adds, arterial tissue is so fragile that even emergency clot-removing intervention can lead to a dissection. “It isn’t always possible to know which came first, but we are sure that without the intervention, Chelsy would have had a much different outcome.” Dr. Alexander says Chelsy’s youth is on her side. “We know the brain can create new connections, and this is especially true in young people. Sometimes we see amazing recoveries. At the very least, we hoped to prevent significant swelling in Chelsy’s brain and give her a fighting chance.”
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Chelsy regained about 70 percent of her vocabulary within a few months. One day she went in for lunch at the Marie Callender’s where she used to bartend, and her boss said, “You’re doing great. You can come back to work now.” “Her regular customers have been like one huge supportive family,” says Kathy. “That has been a big help.” Chelsy says everyday activities like counting money or texting remain tough. She feels frustrated when she has to pause for words or when she utters them out of order or not in the tense she intended. But going back to work was good for her rehabilitation. “I’m moving and I’m talking to people, which helps my speech. But it’s hard now,” admits Chelsy, who sometimes stops in midsentence to say, “I can’t say it.” It’s easier when she slows down her speech. She sometimes questions the progress others see in her recovery, but then laughs about her own impatience. Physically, she’s strong. She can bowl and golf with no problem. And although she hasn’t regained normal sensation on her left WINTER 2016 | DISCOVERIES |
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side, she has learned to adapt. At work, Chelsy carries trays of drinks on her left hand and serves with her right. But since she can’t feel the tray, she uses her eyes to track its position. The words “at work” are a key part of Chelsy’s story, says Dr. Lyden: “Her stroke was quite severe, and it would not have reversed without intervention. If she had not been treated, she would be gravely disabled and probably living in a nursing home today, if she lived this long.”
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Dr. Lyden acknowledges that scientists don’t know all the reasons for the increased incidence of stroke among younger people. Dozens of rare causes may be to blame, but arterial dissections are definitely a significant factor. Unlike Chelsy’s probable dissection, which occurred within the more protective confines of the skull, many are found in an artery of the neck. In a small number of cases, an underlying connective tissue disorder contributes, but dissections can occur spontaneously, for no apparent reason. Spontaneous dissections are estimated to cause only about 2 percent of all strokes — but possibly up to 25 percent of those in people of young and middle age. “I think many Baby Boomers are hesitant to accept the physical limitations of getting older,” Dr. Lyden says. “I’ve treated men in their 50s who fell while surfing, skiing, or playing basketball and suffered strokes caused by arterial dissections. With more people remaining active — and maybe imagining themselves eternally young — we’re seeing more injuries, more dissections, and more strokes.” He adds that even yoga moves, chiropractic manipulations, and leaning back into a beauty parlor sink have been known to precede dissections. According to Dr. Lyden, another insidious risk factor is the migraine headache. While risk is only slightly increased and the reasons are unclear, experts are seeing more migraine-related strokes — especially when the headaches include visual or other sensory disturbances. “Headaches go by different names, such as tension, sinus, and cluster, but any headache that occurs regularly — weekly, monthly, or four or five times a year — is a form of migraine, and migraines cause chemical changes in the brain that we believe increase risk for stroke,” Dr. Lyden says. A 2007 study found that using cocaine or methamphetamines increases stroke risk — and the rising abuse of these substances is leading to more strokes among young people. A study presented at the 2013 International Stroke Conference also showed a strong link between marijuana smoking and suffering a stroke. And although there are claims that marijuana can actually improve stroke recovery, a recent report published in Stroke shows a causal link between marijuana use and the incidence of stroke. Dr. Lyden cautions that drugs don’t have to be illegal to be
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“We still have much more to learn about many of the substances we ingest and their impact on stroke risk.” — Patrick Lyden, MD
ill-advised. Synthetic marijuana, sometimes referred to as “spice” or “legal weed,” can be found in the guise of potpourri on store shelves, although federal and many state regulations have been enacted to prohibit the sale or possession of some synthetic substances. A report by the Substance Abuse and Mental Health Services Administration linked synthetic marijuana to 11,406 emergency department visits in 2010. That number more than doubled to 28,531 the following year. Adverse effects included severe agitation, anxiety, nausea, vomiting, racing heartbeat, elevated blood pressure, tremors, seizures, hallucinations, paranoid behavior, unresponsiveness, and even death. Recently, concerns have been raised about weight-loss and energy-gain dietary supplements with a so-called natural ingredient that contains the chemical BMPEA, which is considered nearly identical to amphetamine. The Canadian government removed such supplements from stores and issued a health alert to consumers: “Amphetamine stimulants can increase blood pressure, heart rate, and body temperature; lead to serious cardiovascular complications (including stroke) at high doses; suppress sleep and appetite; and be addictive.” In the U.S., the FDA has yet to recall the products or issue a public health alert. Dr. Lyden says even common health food store products and energy drinks can contain ingredients mimicking the effects of amphetamines. “Guarana, ginseng, and gingko can affect heart rate, blood pressure, and blood clotting. For healthy people, and in limited amounts, herbs may be harmless or even beneficial, but people with medical problems and those taking other medications should be especially wary.” Even those innocent-looking cans of soda in your refrigerator may not be so harmless. “Surprisingly, a recent study found an association between daily drinking of soda — even diet soda — and increased stroke risk,” Dr. Lyden says. “The research appears sound, although it needs to be substantiated in larger studies. All of this evidence seems to underscore two things: There’s something to be said for moderation, and we still have much more to learn about many of the substances we ingest and the impact they have on stroke risk.”
LEARN MORE
Find out more about disease prevention and control and the Campaign for Cedars-Sinai at giving.cedars-sinai.edu
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Chelsy’s family is set for a cruise to Alaska soon — consolation for the Christmas missed when attention was focused on her survival and recovery. She looks forward to baseball season and hopes to find time to catch a Red Sox game or two on TV. Chelsy’s strides toward recovery have taken a family team effort with Kathy often at the center. When Chelsy falters in finding a word, Kathy assists, but she also en-
courages her daughter to push herself to complete her own sentences. What Chelsy learns in rehabilitation, she practices with her mom at home. And when her daughter feels discouraged, cheerleader Kathy provides perspective. “Chelsy doesn’t see the recovery as much as the rest of us do, and ‘patience’ is not one of her words,” says Kathy. “But the brain is such an amazing thing to behold.” She wraps an arm around her daughter’s shoulder and adds: “After just a few months, look at you! I just can’t get over it.”
DROP THE BOWL OF SODIUM-RICH, NUTRIENT-LACKING NOODLE SOUP AND NOBODY GETS HURT — OR HOW TO PREVENT A STROKE Your grandparents don’t have to worry about the stroke risks associated with birth control pills or pregnancy. They’re probably not involved in kickboxing, surfing, or other strenuous activities that can lead to a tear in the lining of a neck artery, which can bring about a stroke. And chances are that if a congenital heart defect was going to allow a clot to travel to their brains, it would have already happened. Laurie Paletz, board-certified registered nurse, public health nurse, and coordinator of the Stroke Program at CedarsSinai, says that some conditions that raise the risk of a stroke — such as heart defects — cannot be avoided or even detected, but, luckily, young people can take steps to reduce other risk factors. Many are the same health-conscious measures their grandparents have already adopted. “We call high cholesterol, high blood pressure, and diabetes the trifecta because this combination puts people at high risk for stroke at any age,” says Paletz. In a 2011 article in Annals of Neurology, a group of experts analyzed hospital records of young stroke patients over a 13-year span. “Hypertension, diabetes, obesity, lipid disorders, and tobacco use
were among the most common coexisting conditions, and their prevalence increased from 1995 to 2008 among adolescents and young adults (aged 15 to 44) hospitalized with acute ischemic stroke.” Paletz urges young people to review their health habits and take the following steps:
• Avoid alcohol and drugs. • If you smoke, stop. And
don’t assume that electronic cigarettes and “vaping” — inhaling small amounts of vaporized nicotine — are without risk. If you don’t exercise, start. Aim for 30 minutes a day, most days. If you eat sugary, salty, high-calorie foods, cut back — way back. Fruits, vegetables, and whole grains are a healthier foundation for your heart and brain. If you get migraines or other recurring headaches, see a doctor and follow up regularly. Even if you don’t get headaches, make a doctor’s appointment if you haven’t had one in a while.
• •
• •
“How many college students go to the doctor? They saw doctors when they were kids, and maybe they got physicals if they were involved in sports, but young adults tend to take their health for granted,” says Paletz, who chairs a task force for the national Comprehensive Stroke Centers certification program and who recently published an article on preventing strokes related to deep vein thrombosis. “Young people can have stroke risk factors and never know until it’s too late,” she adds. Although about one-third of
such stroke survivors end up with long-term disabilities, it’s not all bad news. “When young people suffer strokes, they have healthy vessels around the dead brain tissue that can create new synapses and new fibers much faster than in elderly patients, so functional outcomes in the young population are better,” she says. “We also have new therapies that didn’t exist even a few years ago. Still, by far the best way to deal with a stroke is to prevent it from happening in the first place.” — Kevin McClanahan
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Dr. Black and his team at Cedars-Sinai pioneered a novel, noninvasive, and relatively inexpensive, experimental imaging technology that scans the retina to detect the amyloid plaque that is associated with Alzheimer’s disease — even before the plaque builds in the brain. This method — now in clinical trials in the U.S. and Australia — can be employed on a much larger scale than PET scan and spinal tap screenings. It also appears to identify brain plaque buildup before patients become symptomatic. In addition, its high resolution can help reveal whether specific interventions are working. If the device receives FDA approval, it could offer an easy, painless, widely available method for early-detection screening. This in turn could lead to intervention with lifestyle modifications and eventually medications to stop or slow the disease.
Alzheimer’s is the nation’s sixth leading cause of death — and the only one in the top 10 that cannot yet be prevented, cured, or even slowed. More than 5 million Americans have Alzheimer’s today, with triple that number expected by 2050. Meanwhile, the number of people worldwide with dementia is expected to climb to 76 million by 2030.
Every 67 seconds, someone in the United States is diagnosed with Alzheimer’s.
One in three seniors dies with Alzheimer’s or another form of dementia.
U.S. deaths from Alzheimer’s disease rose by 71 percent between 2000 and 2013, while those attributed to heart disease, the No. 1 killer, dropped 14 percent.
Identifying patients who are in the pre-disease state is critical.
6. Early Detection
1. Growing Crisis
BY SUSAN L. WAMPLER AND STAN WEDEKING
The insidious nature of Alzheimer’s disease — with onset starting many years before symptoms appear — has reinforced the sense that it strikes at random, without warning or recourse. However, hope exists, with a growing number of experts arguing that the course of the disease can be changed, provided it is diagnosed early enough.
Path to Prevention
Evidence shows that interventions during the pre-Alzheimer’s stage of mild cognitive impairment can significantly affect the disease’s process. Steps you can take to slow or prevent cognitive decline include:
9. Proactive Precautions Manage your blood sugar. Most Alzheimer’s patients have higher-than-normal blood-sugar levels or fullblown diabetes. Emerging research shows that ingesting large amounts of sugar may trigger Alzheimer’s brain changes.
The cost of treating all Americans with Alzheimer’s is expected to skyrocket from $226 billion today to more than $1 trillion (in current dollars) by 2050.
Alzheimer’s is the nation’s most expensive condition, with direct costs of $226 billion expected in 2015. Caregivers of Alzheimer’s patients provided 17.9 billion hours, or $218 billion, in unpaid care in 2014. According to the Alzheimer’s Association, those caring for patients with Alzheimer’s and other forms of dementia incurred their own related healthcare costs of $9.7 billion in 2014.
3. Economic and Personal Toll
Women in their 60s are twice as likely to develop Alzheimer’s during their lifetimes as they are to develop breast cancer.
Of the 5.1 million people age 65 and older with Alzheimer’s in the United States, 3.2 million are women and 1.9 million are men.
Women account for almost two-thirds of Alzheimer’s patients in the U.S. A woman’s estimated lifetime risk of developing Alzheimer’s at age 65 is one in six, compared to only one in 11 for a man.
2. Higher Female Risk
Adopt a Mediterraneanstyle diet. Eat more vegetables and fatty fish such as salmon, herring, mackerel, or tuna (baked or broiled instead of fried), and drink more juices, such as pomegranate, blueberry, and grape.
Get 30 minutes of safe, moderate-to-vigorous exercise on most days of the week as well as engage in activities that improve strength, flexibility, and balance.
Although there is no cure, the U.S. Food and Drug Administration (FDA) has approved five medications to treat Alzheimer’s symptoms. These drugs function either by impeding the disease’s breakdown of acetylcholine, a neurotransmitter associated with memory and thinking, or by regulating glutamate, another neurotransmitter crucial to cognition but that can kill brain cells if it builds up too much.
5. Treating Symptoms
250 clinical trials to halt or cure Alzheimer’s 0 successes
Schedule an appointment with a neurologist if you notice memory loss or other worrisome cognitive changes. We all lose our keys or forget a birthday occasionally, but life-affecting memory lapses should be investigated. Even if you are only in your 30s or 40s, consider seeing a neurologist if you have a family history of Alzheimer’s.
Unique to the Alzheimer’s Prevention Program is the focus on a variety of disease pathways, including inflammation and metabolic processes, rather than just the amyloid pathway traditionally studied. Investigators at Cedars-Sinai are planning to test the application to Alzheimer’s of drugs already on the market for other conditions. One may reverse insulin resistance, thought to play a role in Alzheimer’s, and another is used in multiple sclerosis to modulate the immune system and may increase clearance of amyloid plaques associated with Alzheimer’s.
8. Innovative Investigations
Cedars-Sinai launched the Alzheimer’s Prevention Program, which focuses on screening and providing comprehensive care for patients in the pre-disease state. Directed by Dean Sherzai, MD, PhD, the program identifies at-risk patients and those in the disease’s early stages, when treatments can have the most impact. It then provides patients and families with personalized approaches, long-term care, education, and access to a network of community support. The program also serves as a hub for testing experimental Alzheimer’s drugs.
7. Comprehensive Care
Give your brain regular workouts. Dr. Sherzai suggests listing 10 mental activities that you enjoy and then engaging in three or four every day. Hobbies requiring mind-hand coordination also engage memory, problemsolving, spatial visualization, and other skills. Don’t depend solely on crossword puzzles and Sudoku, which get easier with practice and only target certain parts of the brain.
To date, nearly 250 different clinical trials have tested new treatments for Alzheimer’s — and all have failed. Even after showing promise in animal models, the approximately 50 drugs developed so far as potential cures have been unsuccessful in humans. According to Keith L. Black, MD — chair and professor of the Department of Neurosurgery, director of the Maxine Dunitz Neurosurgical Institute, and the Ruth and Lawrence Harvey Chair in Neuroscience — many of these trials likely failed because they focused on patients who were already symptomatic, which meant the research was being conducted too late in the disease process.
4. Drug Failures
PROSTATE CANCER CAN OFTEN BE MANAGED WITHOUT AGGRESSIVE SURGERY OR RADIATION — AS LONG AS MEN ARE WILLING TO TAKE CHARGE OF THEIR DISEASE AND MAKE SOME SERIOUS LIFESTYLE CHANGES.
By JASMINE AIMAQ • Illustrations by MARK SMITH
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itting in his doctor’s office, Charles Trevino heard the words no one wants to hear: “It’s prostate cancer.” His medical team proposed an aggressive approach, starting with a prostatectomy, a complex procedure in which the prostate is removed. Then 64, Charles was reluctant. On top of the usual risks associated with surgery — such as infection, complications, and an uncertain recovery — he was worried about side effects such as incontinence and erectile dysfunction. But watchful waiting — taking no action except monitoring symptoms — seemed risky, too, even though his tumor was localized and low-grade. Afraid for her husband’s life, Carmen Trevino was on the doctors’ side: Get rid of it, she urged. A year later, Charles has still not gotten rid of the cancer. If things keep going the way they have, he never will. And that’s okay with him. In many cases, prostate cancer patients undergo surgery, radiation, or hormone therapies. However, a growing body of research suggests that not only are these treatments unnecessary for the many men whose cancer is low-grade and slowgrowing, they may actually do more harm than good. Charles is part of a wave of prostate cancer patients and doctors who are opting for a new course that may soon become the norm: active surveillance, an approach often misunderstood, even by those who are aware of it. Active surveillance consists of much more than sitting back and monitoring tumor growth. It’s partly about cutting-edge diagnostics and knowledgeable physicians who aren’t afraid to think outside the box. It’s also about empowering patients by putting them in charge of their prostate cancer and their overall health so they can ward off the real killers, like heart disease. In short, active surveillance is a next-generation answer to a central question in healthcare: How do you save lives while avoiding needless interventions and ensuring that patients enjoy a good life?
Soft Power:
You Don’t Always Need a Sledgehammer Consider this: More men are diagnosed with prostate cancer than ever before. That’s actually good news. For one thing, people are living longer, which exposes them to more age-related diseases like prostate cancer. More importantly, the advent of prostate-specific antigen (PSA) testing in the late 1980s has made early detection easier. This blood test means doctors have a better chance of detecting prostate cancer, starting treatment promptly on aggressive tumors, and closely monitoring those with a favorable risk profile — patients with tumors that, if left
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untreated, would not spread quickly or pose a threat to health. Many studies, including one published in Cancer Research in 2013, indicate that the vast majority of prostate tumors grow slowly and aren’t fatal. Prostate cancer kills fewer than 11 percent of its victims in the U.S., according to the National Cancer Institute and the American Cancer Society. Yet 90 percent of men diagnosed undergo some combination of surgery, radiation, and hormone therapy, which is often unnecessary and can result in serious side effects that noticeably diminish quality of life. Why is this? The answer has to do with an entrenched attitude toward treatment and the limits of scientific knowledge and technology. Understandably, the established medical response has been to risk overtreating and over-testing rather than undertreating. And of the roughly 221,000 men in the U.S. who will be diagnosed with prostate cancer this year, some might agree to a decline in quality of life if the trade-off is survival. Surgery and radiation are not always the most precise tools for treating cancer, but they can be very effective, and given what was known about cancer until recently, they were the best options for many people. “When all you have is a sledgehammer, everything looks like a nail,” explains Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, and the Warschaw, Robertson, Law Families Chair in Prostate Cancer. Fortunately, these mindsets are rapidly changing. Thanks to breakthroughs in personalized medicine and diagnostic technology, the sledgehammer approach, while still important, isn’t the only tool available. One major advance is something doctors and patients already take for granted: imaging technology. Highresolution MRIs help doctors measure and track a tumor’s size, location, and growth pattern with unprecedented precision. PSA tests and increasingly sophisticated imaging have led to considerable improvements in detection and treatment but have brought with them an additional problem: overdiagnosis.
Active surveillance is more than sitting back and monitoring tumor growth. It’s about cuttingedge diagnostics, knowledgeable physicians, and empowered patients.
Not to be confused with misdiagnosis — which is, as the name implies, an incorrect identification of a disease — overdiagnosis refers to a correctly diagnosed disease that is approached as if it were life-threatening when it probably is not. The prevailing philosophy is that, with enough screening, we can identify diseases like cancer or heart disease early enough to treat them before they become life-threatening. In recent decades, diagnostic tools — ranging from blood and genetic tests to ultrasounds and mammograms — have led to a dramatic improvement in the detection of many diseases. But despite an aggressive approach to prostate cancer, many experts note that the decline in mortality has not been dramatic enough to justify the risks involved in screening and intervention — such as false diagnoses, the cumulative effects of radiation, and the side effects of surgery or hormone therapy. An old-fashioned digital rectal exam is how many prostate
tumors used to be detected. However, with the advent of PSA, tumors can often be discovered before they grow large enough to be noticeable during a traditional exam. Once an abnormality is found, a doctor may recommend an ultrasound-guided biopsy, although MRI guidance may sometimes be used instead. The results are reviewed by a pathologist, who determines if cancer is present. If so, the pathologist also determines how aggressive the tumor is, based on the so-called Gleason score: The higher the score, the more likely the tumor is to spread. If the PSA results are somewhat elevated but not alarmingly high, and the Gleason score is below 7, no further evaluation is needed. For men with high PSAs and Gleason 8–10 tumors, however, doctors should advise further imaging — including a bone scan and either an MRI or a CT scan — to investigate whether the tumor has spread. “We’re hoping for a Gleason score below seven,” Dr. Freedland says. “If we get it — and we often do — we can start telling the patient the good news: The tumor doesn’t appear to be aggressive, and active surveillance may be an option.”
Patient Power:
Using the Active Voice Doctors play a fairly straightforward part in active surveillance of prostate cancer. Once diagnosed, eligible patients at Cedars-Sinai undergo a PSA test and rectal exam every three to six months, an MRI every six to 12 months, and a biopsy every year, although the frequency of these tests is continually being refined as new information becomes available and is tailored to the individual patient. For example, if a patient has a PSA that is stable, an MRI that reveals no cancer, and a repeat biopsy a year later showing no cancer — cancers do not disappear, but can become small enough to be undetectable — annual biopsies may not be necessary. The patient’s role is where the word “active” really applies, as Charles discovered when he came to Cedars-Sinai. From the start, he knew he wanted to explore options other than surgery, but his doctor was uneasy with active surveillance and referred him to the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, where a team of specialists — including Dr. Freedland; Hyung Kim, MD, director of Academic Urology and Medallion Group Chair in Urology; WINTER 2016 | DISCOVERIES |
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Howard Sandler, MD, chair of Radiation Oncology and the Ronald H. Bloom Family Chair in Cancer Therapeutics; and Edwin Posadas, MD, director of Urological Oncology — has a proven track record with this approach. Charles, a former educator with a warm smile and thick silver hair, came in and tried not to be overwhelmed. “After 30 years of marriage, six children, and seven grandchildren, I thought I was prepared for anything,” says Charles, “but prostate cancer came as a shock and a source of confusion.” He had a list of questions, trying to make sense of conflicting information. For instance, if his cancer was low-risk, why did so many doctors seem so eager to operate? Dr. Kim had heard the question many times. He reassured his patient, taking the time to explain the various steps and options in detail. “Charles needed to be sure that the approach I was recommending was safe and scientifically valid,” says Dr. Kim. As he entered one of the most crucial partnerships of his life, Charles soon learned that the program’s success was largely up to him. The team of professionals he chose would hold up their end of the bargain, but Charles would have to fulfill the role assigned to him: taking an active part in making real, tangible changes in his life. Like everyone, Charles had heard it a thousand times: To be healthier, you need to commit to fitness and a sound diet. “The advice often falls on deaf ears until a disease with a scary name finally makes an appearance,” says Dr. Freedland, whose research focuses on the role of diet, lifestyle, and obesity in the development and progression of cancer. “Finding out that you have cancer can really bring it home.” Ironically, that’s not because the cancer is likely to kill the patient. Prostate cancer patients are far more likely to die of heart disease — the No. 1 cause of death in the U.S. — than any other health condition. The more intriguing fact is that men with prostate cancer are at higher risk of heart disease than those who are cancer-free. Metabolic syndrome, which entails serious dangers from high blood pressure to Type 2 diabetes, is also more prevalent among men who have prostate cancer. Researchers are investigating why these individuals are more vulnerable, but whatever the reason, they need to be especially vigilant about heart health. So rather than viewing a low-risk prostate cancer diagnosis as nothing but bad news, Dr. Freedland encourages his patients to see it as a chance to implement some much-needed changes and prevent truly deadly diseases from encroaching. “Making a change can give you a new lease on life,” he says. “And as it turns out, what is heart healthy is also prostate cancer healthy.” Shedding excess pounds can help prevent cardiovascular disease, but weight loss is also one of cancer’s natural enemies. Unlike surgery, chemotherapy, radiation, and other tumor fighters, weight loss does not require advanced medical degrees. It is in the hands — and the body — of the patient. Its beneficial effects appear to be twofold, according to Dr. Freedland, who
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“Health advice often falls on deaf ears until a disease with a scary name makes an appearance.” — Stephen Freedland, MD
helped lead a study showing that obesity is associated with a higher risk of aggressive prostate cancer and that weight loss can play a positive role. First, losing weight may reduce the risk of cancer developing in the first place. Second, early data suggests it might prevent an existing low-grade tumor from becoming aggressive. That’s not only true of prostate cancer. Postmenopausal breast cancer, as well as cancers of the colon, esophagus, endometrium, and kidneys, all appear linked to excess weight, and dropping that weight may help. In a study by the American Cancer Society and co-authored by Dr. Freedland, 70,000 overweight men were tracked over 10 years. Those who lost an average of 11 pounds had a 40 percent lower risk of developing aggressive prostate cancer. “The findings are preliminary,” cautions Marc Goodman, PhD, co-director of Cancer Prevention and Genetics at the Samuel Oschin Comprehensive Cancer Institute. “But there is good reason to believe that weight loss is an important tool against various cancers. It’s certainly an important part of active surveillance.” Following Dr. Kim’s suggestion, Charles joined the Men’s Eating and Living (MEAL) study at Cedars-Sinai. The study investigates whether a plant-based diet, along with a healthy lifestyle, can help decrease disease progression and anxiety in men being treated with active surveillance. He stuck to the program, decreasing his reliance on what he calls “the classic Latino cuisine,” including rice, beans, and tortillas. Within one year, he shed 20 pounds and reduced his waist size from 40 inches to 38. More importantly, his cancer remains under control. Many patients feel better when they lose weight and become more active, but with active surveillance, something additional changes. According to Dr. Kim, “Instead of feeling like a victim, the patient is now in the driver’s seat.” That may be especially important for men. Sociological sur-
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Find out more about disease prevention and control and the Campaign for Cedars-Sinai at giving.cedars-sinai.edu
Eric Reed
veys indicate that, on average, men are less likely to visit the doctor, pursue medical treatment, ask for help, or even admit to symptoms. Being given a set of instructions and told what to do can be especially difficult for some older men who may have held positions of authority in their professional lives. Says
Active surveillance patient Charles Trevino enjoys cooking healthy meals with his wife, Carmen, and remains physically active to decrease his risk of disease progression.
Dr. Freedland: “With active surveillance, we’re telling the patient, ‘Here is what we can do, and here is what you can do. We’re going to do our job. The rest is up to you.’”
Following Up and Catching On Some 20 to 30 percent of active surveillance patients will go on to more invasive treatment within two or three years, either because the cancer becomes aggressive — as revealed by a rising Gleason score or PSA levels — or because the patient tires of the active surveillance program and is unwilling to sustain the lifestyle changes or deal with the regularly scheduled tests and the “what ifs” as they wait for results. Ultimately, the decision of how to proceed must be made by each patient and his doctor, but, as Dr. Freedland explains, “Active surveillance involves very little risk, because, at Cedars-Sinai, we monitor the patient closely with cutting-edge diagnostic tools.” The data appears to confirm his claim. Investigators at Johns Hopkins University conducted a long-term study evaluating 10- and 15-year survival rates for 1,298 favorable-risk prostate cancer patients who were diagnosed in 1995 or later and adopted the active-surveillance protocol. Cancer-specific survival — which means that the patient did not die of prostate cancer — was 99.9 percent at both 10 and 15 years. Metastasis-free survival — where the patient survived and the cancer did not spread to other parts of the body — was 99.4 percent at 10 and 15 years. For cases where the patient opts for surgery after coming off active surveillance, success rates are the same as for patients who underwent an operation for an aggressive tumor right after they were diagnosed. Despite the safety of active surveillance, not everyone is on board. The idea is still young. Many doctors faced with favorablerisk patients still reach for more traditional therapies. Word is spreading, however. More and more, physicians at Cedars-Sinai see patients who have sought them out and are prepared to do what it takes to slow their cancer’s progress. Often, these are men who were recently diagnosed, have done some research online, and found their own doctors unfamiliar with — or unwilling to consider — active surveillance. Today, Charles works out regularly at the gym and takes long walks around the Rose Bowl in Pasadena, one of his favorite places. He eats lots of fresh leafy greens, consumes very little red meat, and drinks alcohol in moderation. Active surveillance represents not only a pivotal moment in prostate cancer treatment but a big step toward next-generation, high-value healthcare. It’s also a reminder of the old adage about tough times and silver linings: Charles knew his life would change after the prostate cancer diagnosis. He just didn’t know it would change for the better. WINTER 2016 | DISCOVERIES |
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JOIN OUR PATIENT ADVISORY PANEL As a leader in delivering quality care, Cedars-Sinai is always looking for new ways to enhance our patients’ experiences. This involves paying close attention to your opinions about what we’re doing right and how we can do better. We invite you to share your unique perspective through our online Patient Advisory Panel. This is an opportunity to influence the future of healthcare in ways that can have far-reaching benefits — for you, your family and many others. Plus, participation has additional perks. When you join our panel, you will have the chance to win $100 prizes every time you choose to complete a survey. Go to cedarssinaipanel.com/joinnow to join our panel by completing a simple introductory survey.
Faculty News WINTER
2016
37 NEWS AND AWARDS | 39 NEW FACULTY | 39 IN MEMORIAM Richard Bergman, PhD, received the Albert Renold Award from the American Diabetes Association for his outstanding work training new generations of diabetes researchers and facilitating scientific investigation in the field. Director of Cedars-Sinai’s Diabetes and Obesity Research Institute and the Alfred Jay Firestein Chair in Diabetes Research, he has trained and mentored numerous PhD students and postdoctoral fellows in basic and clinical science. Many of his students have gone on to make significant contributions of their own to the study and treatment of diabetes.
The graduates of the Class of 2015 Cedars-Sinai Graduate Program in Biomedical Science and Translational Medicine (from left): Jessica Beach, PhD, Felix Alonso-Valenteen, PhD, Candy Bedoya, PhD, I-Farn Lei, PhD, and Sara Pollan, PhD
Thomas Neerken
New PhDs Take the Stage Class speaker Jessica Beach, PhD, articulated the pride and joy felt by her graduating cohort in the Cedars-Sinai Graduate Program in Biomedical Science and Translational Medicine when she introduced herself as “Doctor Jessica Beach, a proud member of the Cedars-Sinai Class of 2015.” Jonathan Thomas, PhD, JD, chair of the governing board of the California Institute for Regenerative Medicine (CIRM), delivered the commencement address to this third graduating class. His remarks lauded the “outstanding work” of Cedars-Sinai’s PhD researchers. In an interview after the ceremony, Dr. Thomas added that the medical center was “very important” to
CIRM’s work in developing promising stem cell technologies through partnerships with academia and industry. Cedars-Sinai fields an “absolutely first-rate team,” he said. Along with Dr. Beach, the 2015 graduates are Felix Alonso-Valenteen, PhD; Candy Bedoya, PhD; I-Farn Lei, PhD; and Sara Pollan, PhD. Their research interests include chemotherapy resistance, nanoparticle medicine, cardiovascular disease, neuroscience, and regenerative medicine. In his welcoming remarks, Cedars-Sinai President and CEO Thomas M. Priselac told the new PhDs, “You are vital because you subscribe to the belief that the highest calling of biomedical
Sumeet S. Chugh, MD, has been awarded a $2.36 million grant by the National Heart, Lung, and Blood Institute to develop prevention strategies for sudden cardiac arrest, which kills an estimated 300,000 Americans each year. With the new grant, Dr. Chugh — associate director of the Cedars-Sinai Heart Institute and the Pauline and Harold Price Chair in Cardiac Electrophysiology Research — and his team will study patients aged 35–59 in an effort to predict who is most likely to
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Faculty News
experience sudden cardiac arrest, which has less than a 5 percent survival rate. The Cedars-Sinai Heart Institute bestowed its 2015 Eliot Corday, MD, International Prize in Heart Research on Alain Cribier, MD, professor emeritus at the University of Rouen in France, for his achievements in nonsurgical cardiac interventions. Dr. Cribier credits Cedars-Sinai with launching his illustrious career in science: He was a research fellow in the laboratory of cardiologist William Ganz, MD, from 1976–77. Dr. Ganz, along with cardiologist H.J.C. (Jeremy) Swan, MD, invented the groundbreaking Swan-Ganz catheter for assessing heart function. Dr. Cribier calls the two cardiologists his “heroes of medicine.” Kimberly Gregory, MD, MPH, director of Maternal Fetal Medicine and vice chair for Women’s Healthcare Quality and Performance Improvement in the Department of Obstetrics and Gynecology, received a grant to launch a study into the healthcare priorities of pregnant women, funded by the Patient-Centered Outcomes Research
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Institute. The nonprofit organization is authorized by Congress to fund research that helps people make informed healthcare decisions and improves healthcare delivery and outcomes. The expressed priorities of mothers will be compared among various communities, including racial and ethnic groups, educational levels, and women with or without previous childbirth experience. Stanley C. Jordan, MD, director of Pediatric and Adult Nephrology, Kidney Transplantation and Transplant Immunology, and director of the Kidney and Pancreas Transplant Center, received Cedars-Sinai’s inaugural Prize for Research in Scientific Medicine (PRISM) for his groundbreaking contributions to the treatment of organ transplant patients. Dr. Jordan’s research led to a drug therapy protocol that significantly reduces the risk that a patient’s body will reject a transplanted kidney. Thanks to his work, 60 percent of patients once considered unsuitable for transplant due to the risk of rejection can receive kidneys. The PRISM award recognizes outstanding scientific or medical breakthroughs by Cedars-Sinai faculty,
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particularly bench-tobedside scholarship. Neel R. Joshi, MD, clinical assistant professor in the Department of Surgery, received the 2015 Dr. Kenneth Adashek Surgical Excellence Award in June. The annual honor, which includes $25,000, is presented to a surgeon who has completed a fellowship within the past 10 years and who epitomizes surgical excellence, among other exceptional qualities. It is named for Kenneth W. Adashek, MD — a longstanding attending surgeon at Cedars-Sinai and chairman of the Division of Surgery from 1990 to 1991. Debiao Li, PhD, director of the Cedars-Sinai Biomedical Imaging Research Institute, leads a team that has been awarded a $3.3 million grant from the National Institutes of Health to develop a noninvasive, radiation-free magnetic resonance imaging technique for detecting myocardial ischemia. The condition is a reduction in blood flow that commonly results from coronary artery disease and can lead to heart attack, so early diagnosis could help save lives, according to Dr. Li. Coronary artery disease is the most frequent cause of death for men and women worldwide.
Robert J. Siegel, MD, and P.K. Shah, MD, were honored by the American College of Cardiology in March. Dr. Siegel — director of the Heart Institute’s Noninvasive Cardiac Laboratory and the S. Rexford Kennamer, MD, Chair in Cardiac Ultrasound — received the Distinguished Teacher Award. Dr. Shah — director of the Oppenheimer Atherosclerosis Research Center and the Shapell and Webb Family Chair in Clinical Cardiology — was named a master of the college. Biostatistician Mourad Tighiouart, PhD, was awarded $1.7 million by the National Cancer Institute to study ways to make cancer clinical trials safer and more effective. Dr. Tighiouart, associate director of the Biostatistics and Bioinformatics Research Center at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, will focus on Phase I and II clinical trials that simultaneously test two or more chemotherapy or biologic agents, an increasingly common therapy for cancer patients. His goal is to identify dose combinations that are safe, well-tolerated, and effective. Jennifer Van Eyk, PhD— director of Basic Science Research at the Barbra Streisand Women’s Heart Center, director of
the Advanced Clinical Biosystems Research Institute, and the Erika J. Glazer Chair in Women’s Heart Health — has received a $500,000 Grand Challenge Award as part of the Cardiovascular GenomePhenome Study, a collaborative research effort spearheaded by the American Heart Association. She and her team will advance their study of blood protein biomarkers in people of European, AfricanAmerican, and South Asian descent. The researchers hope to discover protein biomarkers that can predict cardiovascular risk. Shaomei Wang, MD, PhD, PhD, a research scientist at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, has received a $4.9 million grant from the California Institute for Regenerative Medicine to advance her work on retinitis pigmentosa, a degenerative eye disease that causes blindness and affects 150,000 people nationally. The grant will support Dr. Wang’s preclinical studies that center on injecting human neural progenitor cells — similar to stem cells — into the eyes of patients. When used in animal models, this therapy has been shown to slow retinal degeneration and preserve vision.
science lies in its translation — that laboratory discoveries only acquire genuine meaning when they are successfully deployed to heal the human body.” He also praised their tenacity in following “a road less traveled, one where the coin of the realm is precision and endurance.” Addressing the graduates, Shlomo Melmed, MD, professor of Medicine, executive vice president of Academic Affairs, and dean of the Medical Faculty, urged scientific teamwork in an era of big data. The results will create an “atmosphere of genius” by empowering productivity and innovation, said Dr. Melmed, who is also the Helene A. and Philip E. Hixon Distinguished Chair in Investigative Medicine. The June 10 event also marked the
inaugural awarding of the Cedars-Sinai Prize for Research in Scientific Medicine (PRISM). Stanley C. Jordan, MD — professor of Medicine and Pediatrics, director of Kidney Transplantation and Transplant Immunology, and director of Pediatric and Adult Nephrology — received the honor for achievements that include the identification of interleukin 6 (IL-6) as a cytokine responsible for graft rejection in solid organ transplants. Kathrin Michelsen, PhD, assistant professor of Medicine and a research scientist at the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, received the David L. Rimoin Teaching Excellence Award. The Rimoin Award winner is chosen by the PhD candidates themselves.
More than 35 students are enrolled in Cedars-Sinai’s eight-year-old Graduate Program in Biomedical Science and Translational Medicine, which focuses on transforming laboratory discoveries into therapies, treatments, and cures that directly benefit patients. Accredited by the Western Association of Schools and Colleges, the program is overseen by Leon Fine, MD, professor of Medicine and Biomedical Sciences, chair of Biomedical Sciences, and vice dean of Research and Graduate Research Education. The program director is David Underhill, PhD, professor of Biomedical Sciences and Medicine and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease.
New Faculty
Srinivas Gaddam, MD Gastroenterology
Mazen Noureddin, MD Gastroenterology
Daniel Shouhed, MD Surgery
Richard J. Edelman, MD Psychiatry
Eynav Accortt, PhD Obstetrics and Gynecology
Wei Gao, PhD Biomedical Sciences
J. Manuel Perez, PhD Neurosurgery
Monica Sondhi, MD Pediatrics
David S. Gans, MD Nephrology
Simon Gayther, PhD Biomedical Sciences
Nipaporn Pichetshote, MD Gastroenterology
Echo Tan, MD Neurology
Milton D. Heifetz, MD Neurosurgery
Heather Hindo, MD Pediatrics
Helen Pizzo, MD Pediatrics
Nai Yu Tang, MD Pediatrics
Robert Ledner, MD Imaging
Caroline Jefferies, PhD Immunology
Padmesh Rajput, PhD Neurology
Tsuyoshi Todo, MD Surgery
Rashid Massumi, MD Cardiology
Artak Labadzhyan, MD Endocrinology
Chrystal Reed, MD, PhD Neurology
Adriana Vidal, PhD Surgery
Jack Matloff, MD
Shouri Lahiri, MD Neurology
Konrad Schlick, MD Neurology
Janet Wei, MD Cardiology
Abdolsamad Mossahebi, MD Pediatrics
Kate Lawrenson, PhD Obstetrics and Gynecology
Bahareh Schweiger, DO, MPH Pediatrics
Zachary Zumsteg, MD Radiation Oncology
Paul Rudnick, MD Endocrinology
Everardo Macias, PhD Surgery
Anna Selvaggio, MD Pulmonary Medicine
In Memoriam
Jaspreet Mann, DO Neurology
Lili Shek, MD Internal Medicine
Basil Clyman, MD Rheumatology
Melodie Metzger, PhD Surgery
Ayesha Sherzai, MD Neurosurgery
Michael Davidson, MD Cardiology
Christopher Almario, MD Gastroenterology Allen Andres, PhD Molecular and Cell Biology Robert Barrett, PhD Regenerative Medicine Brian Benway, MD Surgery Janine Bilsborough, PhD Digestive Diseases Research Joshua Chung, MD Surgery Timothy Daskivich, MD Surgery Stephen Freedland, MD Cancer Genetics and Prevention
Cardiothoracic Surgery
Sheldon Siegel, MD Pediatrics Gary D. Sugarman, MD Cardiology Lionel A. Walpin, MD Physical Medicine & Rehabilitation
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Opinion
Vaccination and the Challenges of Success
G
rowing up in the 1940s was a dangerous venture: In America, thousands of children died every year from diseases we rarely hear about today. Diphtheria took the lives of nearly 2,000 — the same number that succumbed to paralysis from polio. That changed with widespread vaccination. The effect has been so dramatic that the impact is still evident in our day-to-day lives. When was the last time you knew someone diagnosed with diphtheria? Or polio? Or tetanus? These diseases are now so uncommon, most young American doctors have never seen a case. This success should be celebrated. Yet, when I speak to parents about vaccination, the response I hear is often less than enthusiastic. I hear concerns about safety and questions about necessity. Vaccination rates in some communities have fallen to dangerously low levels. In 2014, the U.S. experienced 23 outbreaks of measles, mumps cases doubled from the previous year, and the California pertussis epidemic claimed the lives of three infants. How do we explain this discrepancy? First, vaccine success is quiet — it doesn’t make headlines when people don’t get sick. We forget that nearly one in five childhood deaths worldwide is due to vaccinepreventable diseases that are just an airplane flight away. Measles alone kills more than 16 children every hour around the globe. Second, although success is quiet, side effects are not. Like any medication, vaccines are not 100 percent effective, and side effects do occur, albeit rarely. However, we must keep our perception of risk within
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| DISCOVERIESMAGAZINE.ORG
By JONATHAN GREIN, MD
context. When a disease is common and an effective vaccine is 99.99 percent safe, vaccination feels safe to people. Yet, when the disease becomes less common, any risk of vaccination (even 0.01 percent) feels unsafe. The problem is that the risk of disease is still present. It just doesn’t feel that way because the disease itself has grown so rare in our society. Finally, we have been inundated with a false balance of information. The media often cover scientific issues in the same format as political debates — both sides of an argument get equal time. This neglects the tremendous balance of rigorous scientific evidence showing that vaccines are safe and effective. This issue is too important to be swayed by misinformation and fear. A recent Centers for Disease Control and Prevention analysis reports that vaccinating each child born in the U.S. every year would prevent approximately 42,000 deaths and 20 million cases of disease. By maximizing vaccination rates, we also protect those who cannot get vaccinated for medical reasons or who don’t have the immune system needed for vaccines to work. It’s time for the misleading “debate” over vaccination to end and for meaningful dialogue to start among caregivers and skeptical parents. We will likely never see a more effective diseaseprevention measure. It’s time to wield and affirm the success and power of vaccination. Jonathan Grein, MD, is associate director of the Department of Hospital Epidemiology at CedarsSinai. He is board-certified in Internal Medicine and Infectious Diseases.
Cedars-Sinai
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CEDARS-SINAI DISCOVERIES
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Cedars-Sinai is a national leader in providing high-quality, patient-centered healthcare encompassing primary care as well as specialized medicine and conducting research that leads to lifesaving discoveries and innovations. Since its beginning in 1902, Cedars-Sinai has evolved to meet the healthcare needs of one of the most diverse regions in the nation, continually setting new standards in quality and innovation in patient care, research, teaching, and community service. Today, Cedars-Sinai is widely known for its national leadership in transforming healthcare for the benefit of patients. Cedars-Sinai impacts the future of healthcare globally by developing new approaches to treatment and educating tomorrow’s physicians and other health professionals. Cedars-Sinai demonstrates a longstanding commitment to strengthening the Los Angeles community through wide-ranging programs that improve the health of its most vulnerable residents.
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IT FIRST STARTS HERE. With hundreds of active research projects going on, it’s the everyday gift that helps fuel our most important medical advancements. Caring people, just like you, contributing to our research team in a vital way that could advance new treatments and technologies to help change lives. That’s because at Cedars-Sinai, every breakthrough begins with you. Learn more about how you can make a gift that is the start of something great, at giving.cedars–sinai.edu. MICHAEL BERNS, CEDARS-SINAI DONOR
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BRAIN QUAKE In This Issue 20 Unbreakable
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28 Path to Prevention
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A newly discovered genetic mutation could lower the risk of Type 2 diabetes, which could open new frontiers in drug development — and open the door to personalized diabetes treatment.
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HOW WE STRIKE BACK. PLUS: ALZHEIMER’S DISEASE PREVENTION P28
When Charles Trevino learned he had prostate cancer, he refused aggressive therapy. Instead, he joined a growing number of men who choose active surveillance — a highly successful, too often misunderstood, approach.
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