19-year-old patient receives rare combination surgery.

Jennifer Golden received the first double lung-liver transplant performed at UCLA.

Jennifer Golden, a 19-year-old college student from Las Vegas, got her Christmas gift early this year — a pair of life-saving lungs and a liver at Ronald Reagan UCLA Medical Center on Dec. 4.

The rare combination surgery, thanks to the gift of one donor, also marked a milestone for the hospital’s organ transplant program: It was the first operation of its kind ever performed at UCLA.

The young woman has a genetic condition called cystic fibrosis, which causes thick, sticky mucus in her lungs that traps infection-causing bacteria. As a result, Jennifer experienced shortness of breath, excess mucus, coughing, an inability to gain weight and diabetes.

Her disease was managed by a routine of “tune-ups” to clear the mucus in her lungs with antibiotics, intravenous medications, physical therapy and other procedures. However, over the years, her lungs developed infections that became increasingly difficult to treat. To make matters more complicated, Jennifer’s liver function was also affected by the disease. By her senior year, she was so sick she could no longer attend high school.

At age 17, with her lungs and liver simultaneously deteriorating, she was told her only chance at life was organ donation.

“I felt every emotion — scared, nervous, but also happy that this could save my life,” Jennifer recalled.

A double lung-liver transplant surgery is rare. According to the most current data available from the United Network for Organ Sharing which manages the country’s organ donation system, only 44 lung-liver transplants have been performed in the United States. It is also unusual for a cystic fibrosis patient to need both lungs and a liver. More commonly, because of the way the disease progresses, the patient needs only one organ or the other.

“Because of her small size and the necessity for both the lungs and liver to be usable, she knew — as did we — that her wait might be long,” said Dr. Sue McDiarmid, professor of pediatrics and surgery, director of the pediatric liver transplant program and Jennifer’s doctor for 10 years.

Meantime, Jennifer’s entire lung and liver transplant team — including surgeons, physicians and anesthesiologists — spent a lot of time planning for her complex surgery. For example, the surgeons decided that the best approach would be for the lung transplant to be performed first.

“We also consulted with reconstructive surgeons to map out where we would make our incisions so that Jennifer’s abdominal muscles, bone and skin would not be impacted,” added Dr. Doug Farmer, professor of surgery and surgical director of the pediatric liver transplant program. “Our goal was to perform the surgery efficiently and with minimal blood loss.”

Two years later, on Saturday, Dec. 3, Jennifer got the call that a donor had been found. She and her mom quickly flew to UCLA while her dad followed behind in the family car.

Jennifer was wheeled into surgery around 4:45 a.m. on Dec. 4. The team’s intense planning paid off, and the 13-hour operation went smoothly.

When Jennifer came out of her surgery, her ability to breath was immediately improved. With the diseased lungs removed, her illness is now gone although her cystic fibrosis is not technically cured since it is part of her genes.

“We are quite optimistic that Jennifer will do well,” said Dr. Abbas Ardehali, professor of cardiothoracic surgery and surgical director of the heart and lung transplant program at UCLA. “This is our mission here at UCLA to expand the horizon of transplant patients we can serve.”

The former high school tennis team captain can now look to the future, and her plans include being with her fiancé, continuing her college studies and hitting the tennis courts again.

She also has a vital message to deliver.

“I hope that if a family out there is ever suffering with the death of loved one, they will consider the priceless gift of organ donation,” Jennifer said. “Someone did that for me, and it saved my life. My family and I cannot thank them enough.”

“Without organ donors and their families,　stories like Jennifer’s would have only tragic endings. Jennifer now breathes with ease — she is pink — her new liver is working very well, and all this because of this one donor whose life lives on in another,” said McDiarmid.

Accomplished UC Irvine scientist and award-winning mentor.

Sheryl Tsai, UC Irvine

Most professors will say that they look at the “Rate My Professor” website with trepidation. It’s easy to get discouraged if a student complains that your grading isn’t fair, or you have dandruff or, even worse, that you’re boring.

Sheryl Tsai has no such fears. Her reviews are unanimous raves, and she has the teaching awards to prove it. “She’s hilarious,” writes one student. “She actually enjoys talking about biology with her students!” writes another.

An associate professor at UC Irvine, Tsai works in the hot new field of chemical biology, harnessing a compendium of scientific disciplines to the task of discovering new drugs.  In 2006, she was named a Pew Scholar for her research on the genetic modification of polyketides, natural products of plants, fungi and bacteria that can form the basis for new treatments for HIV, diabetes and cancer.

Her research has gained international recognition, but she’s just as proud of the teaching awards she’s earned at UC Irvine, including the prestigious Golden Apple Award for Teaching in the Biological Sciences. She mentors five or six students each year through UC Irvine’s Undergraduate Research Opportunities Program.

The UC Berkeley-educated Tsai grew up in Taiwan. (Her first name, Shiou-Chuan, informally became Sheryl after she arrived in the U.S.) By the time she was in high school, cultural and political ferment was loosening the grip of the island’s leaders and, as a result, Tsai says that when she arrived in Berkeley, the famously liberal city felt like home — almost.

Q: Your undergraduate and master’s degrees are from the University of Taiwan. Is university education different there?

A: Most of the professors have Ph.D.s from the United States, so it was very Americanized. Taiwan is a very open country with a big influence from the United States.  I grew up watching “The A-Team” every night.

Q: Berkeley isn’t exactly like the rest of America. Was it a shock?

A: Not really. I think the reason I felt comfortable at Berkeley was the emphasis on social justice. That year, the city of Berkeley increased parking fees, and to show their opposition, people knocked the heads of the parking meters off and planted flowers in them. Everywhere in the city, you saw flowers planted in the beheaded parking meters.

Finding by UC Irvine team could help prevent cardiovascular complications.

N.D. Vaziri, UC Irvine

UC Irvine researchers have uncovered an important source of inflammation seen in people with chronic kidney disease, which is increasingly common due to the epidemic of obesity-related diabetes and hypertension.

Dr. N.D. Vaziri, professor emeritus of medicine and physiology & biophysics, found that CKD causes massive depletion of the key adhesive proteins, called the tight junction, that normally seal the space between the cells lining the intestines. This breakdown in the colon allows the leakage of microbial products and other noxious material into the body’s internal environment, accounting for the persistent systemic inflammation that frequently occurs in CKD patients.

“In fact, low levels of bacterial endotoxins are often noted in the blood of individuals with advanced chronic kidney disease,” Vaziri said. “However, the source and place of entry of these toxins were previously unknown.”

Understanding the connection between CKD and tight junction disintegration, he added, could lead to novel treatments to curb this inflammation and its many adverse consequences. Study results appear online in the journal Nephrology Dialysis Transplantation.

It’s estimated that nearly 25 million people in the U.S. have CKD, and more than 400,000 have end-stage kidney disease requiring dialysis. Many CKD patients develop accelerated cardiovascular disease — the primary cause of premature death in this population — linked to persistent inflammation.

“The relentless inflammation seen in chronic kidney disease has devastating effects on the cardiovascular system and other parts of the body,” Vaziri said.

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UCSF, Kaiser Permanente researchers take aim at genetic links to disease.

An ambitious project, teaming Kaiser Permanente and UC San Francisco researchers, takes aim at genetic links to disease.

At last count, nearly 200,000 members of Kaiser Permanente, one of the nation’s largest health maintenance organizations, had “spit for health” or given blood samples — providing a small supply of their DNA for researchers seeking genetic clues to the causes and prevention of many diseases.

The volunteers are part of the nation’s largest, most thorough effort to identify the genetic variations that underlie the aging process, vulnerability to disease and drug effectiveness.

The project goes well beyond the search for genetic links. It surveys patients’ personal habits, such as smoking, diet and availability of healthy food; it also examines environmental exposures, from pollution and pesticides to housing density and crime.

The research lays the groundwork for understanding how inherited traits and the environment affect health, and how genetic differences influence people’s responses to environmental insults and drug treatments.

Referred to as the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH), it draws on Kaiser Permanente’s voluminous electronic patient medical records, which go back at least 15 years.  It is the world’s largest civilian electronic health record, and it is continuously updated to document the health status of all Kaiser members.

The RPGEH is led by Catherine Schaefer of Kaiser Permanente’s Division of Research and Neil Risch, director of UCSF’s Institute for Human Genetics.

The current phase of the RPGEH is funded by a $25 million grant from the National Institutes of Health. This support so far has enabled the researchers to develop genomic profiles of more than 100,000 RPGEH participants.

“Our goal is to provide a powerful resource for research into the genetic and environmental factors that may affect many common health conditions — such as cancer, cardiovascular disease, asthma, diabetes and mental health disorders,” said Schaefer, RPGEH’s executive director.

“We expect this comprehensive approach will accelerate development of new ways to treat and possibly prevent these conditions,” she said.

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Results of mouse tests show promise for drug development, treatment of diabetes.

Human adipose tissue (fat)

By knocking out a key regulatory protein, scientists at the University of California, San Diego School of Medicine and the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland dramatically boosted insulin sensitivity in lab mice, an achievement that opens a new door for drug development and the treatment of diabetes.

The research, published in Friday’s (Nov. 11) issue of the journal Cell, reveals a new and previously unsuspected role for nuclear receptor corepressor (NCoR), a transcriptional coregulatory protein found in a wide variety of cells.

“Different transcription factors stimulate genes, turning them on and off, by bringing in co-activators or co-repressors,” said Dr. Jerrold M. Olefsky, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego and senior author of the paper. “All transcriptional biology is a balance of these co-activators and co-repressors.”

Olefsky and colleagues focused their attention on NCoR, which was known to be a major co-repressor of Peroxisome Proliferator-Activated Receptor gamma or PPAR-gamma, a ubiquitous protein that regulates fatty acid storage and glucose metabolism, but which also appeared to act on other receptors as well.

“It seemed to be a general purpose co-repressor,” said Olefsky. “It’s unusual for one protein to do so many things. It’s not very efficient and you don’t see it too much in biology.”

The scientists created a knock-out mouse model whose adipocytes or fat cells lacked NCoR. Though bred to be obese and prone to diabetes, Olefsky said the glucose tolerance improved in the NCoR knock-out mice. Moreover, they displayed enhanced insulin sensitivity in liver, muscle and fat, and decreased systemic inflammation. Resistance to insulin, a hormone central to regulating carbohydrate and fat metabolism, is a hallmark of diabetes, as is chronic inflammation.

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Discovery provides insights into interaction between regulated genes and human disease.

Michael Rosenfeld, UC San Diego

Cells develop and thrive by turning genes on and off as needed in a precise pattern, a process known as regulated gene transcription. In a paper published in Wednesday’s (Nov. 9) issue of the Journal of Neuroscience, researchers at the University of California, San Diego, School of Medicine say this process is even more complex than previously thought, with regulated genes actually relocated to other, more conducive places in the cell nucleus.

“When regulated gene transcription goes awry, many human diseases result, such as diabetes, atherosclerosis, cancer and growth defects in children,” said Michael G. Rosenfeld, M.D., a professor in the UC San Diego Department of Medicine, Howard Hughes Medical Institute investigator and senior author of the study. “We’ve shown that rather than being activated at certain, random locations within the cell nucleus, regulated genes can dynamically relocate. The discovery provides a more comprehensive picture of the interaction between regulated genes and human disease.”

Specifically, Rosenfeld and colleagues found that genes regulating cell proliferation responded to growth signals by moving targeted genes from a “silencing environment” in the nucleus called Polycomb bodies to another nuclear compartment called interchromatin granules, which is enriched with activating transcription factors. The movement was precisely guided by two non-coding RNA (ncRNA) molecules called TUG1 and NEAT2.

NcRNA are molecules that are not translated into proteins. In recent years, researchers have ascribed a growing list of duties to them. In this case, Rosenfeld said, TUG1 and NEAT2 move genes to a location in the cell nucleus where they can be more effectively activated and accomplish their function. Cells contain many ncRNAs and it’s likely that others play roles similar to TUG1 and NEAT2 in association with various human diseases.

“A big finding here is the uncovering of a general ncRNA-dependent sensor strategy that relocates a large subset of regulated transcription unit cohorts,” said Liquing Yang, a postdoctoral member of the Rosenfeld lab and co-first author of the study. “Our data suggests that ncRNAs act as regulators and perhaps as modifiers of ‘readers’ and ‘writers’ of the histone code, which implies they have a critical ‘switching’ role in gene transcription regulation.”

“The ability to have signal-dependent relocation of genes in the subnuclear architecture has intriguing implications both in normal regulation and in cancer,” added the other co-first author, Chunru Lin.

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UCSF bioengineer working to create tiny devices that can treat diabetes or kidney failure.

Tejal Desai, UC San Francisco

The same technology used to create integrated circuits may one day be applied to the body to deliver medicine or serve as implants that act as an artificial organ. Tejal Desai, a bioengineer at the University of California, San Francisco, is working with microelectromechanical systems, or MEMS, to create tiny devices that can treat diabetes or kidney failure. But Desai says they’re also looking at different devices which one could potentially inject via catheter.

“Eventually, the goal is to create an implant that actually would just be a simple injection and that injection would be able to have a device,” Desai said. “It’s made out of a really thin film of polymer material and has small channels that can deliver drugs for many months. “

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Adult stem cells can reshape organs in response to changes in the body and environment.

A new study from University of California, Berkeley, researchers demonstrates that adult stem cells can reshape our organs in response to changes in the body and the environment, a finding that could have implications for diabetes and obesity.

Current thinking has been that, once embryonic stem cells mature into adult stem cells, they sit quietly in our tissues, replacing cells that die or are injured but doing little else.

But in working with fruit flies, the researchers found that intestinal stem cells responded to increased food intake by producing more intestinal cells, expanding the size of the intestines as long as the food keeps flowing.

“When flies start to eat, the intestinal stem cells go into overdrive, and the gut expands,” said UC Berkeley postdoctoral fellow Lucy O’Brien. “Four days later, the gut is four times bigger than before, but when food is taken away, the gut slims down.”

Just as in humans and other mammals, O’Brien added, the fly intestine secretes its own insulin. In flies, intestinal insulin seems to be the signal that makes stem cells “supersize the gut.”

“Because of the many similarities between the fruit fly and the human, the discovery may hold a key to understanding how human organs adapt to environmental change,” said David Bilder, UC Berkeley associate professor of molecular and cell biology.

The research will be published in tomorrow’s (Oct. 28) issue of the journal Cell.

Many tissues grow or shrink with usage, including muscle, liver and intestine. Human intestines, for example, regrow after portions have been surgically removed because of cancer or injury, and hibernating animals see their intestines shrink to one-third their normal size during winter.

“One strategy animals use to deal with environmental variability is to tune the workings of their organ systems to match the conditions at hand,” O’Brien said. “How exactly this ‘organ adaptation’ happens, particularly in adult animals that are no longer growing, has long been a mystery.”

Following the surprising discovery of stem cells in the intestines of fruit flies five years ago, O’Brien and Bilder decided to investigate the role of adult stem cells in normal intestinal growth in hopes of finding clues to their role in vertebrates like us.

“I looked at stained stem cells in the fruit fly intestine, and they are studded throughout like jewels. The tissues were so beautiful, I knew I had to study them,” O’Brien said.

O’Brien, Bilder and their colleagues discovered that when fruit flies feed, their intestines secrete insulin locally, which stimulates intestinal stem cells to divide and produce more intestinal cells.

“The real surprise was that the fruit fly intestine is capable of secreting its own insulin,” BIlder said. “This intestinal insulin spikes immediately after feeding and talks directly to stem cells, so the intestine controls its own adaptation.”

Stem cells can divide either asymmetrically, producing one stem cell and one intestinal cell, or symmetrically, producing two stem cells. The team found that, in response to food, intestinal stem cells underwent symmetric division more frequently than asymmetric division, which had the effect of maintaining the proportion of stem cells to intestinal cells, and is a more efficient way of ramping up the total number of cells, O’Brien said.

“Adaptive resizing of the intestine makes sense from the standpoint of physiological fitness,” she said. “Upkeep of the intestinal lining is metabolically expensive, consuming up to 30 percent of the body’s energy resources. By minimizing intestinal size when food is scarce, and maximizing digestive capacity when food is abundant, adaptive intestinal resizing by stem cells helps animals survive in constantly changing environments.”

Bilder and O’Brien’s coauthors on the Cell paper are UC Berkeley staff researchers Sarah S. Soliman and Xinghua Li.

The work was supported by the National Institutes of Health and, for O’Brien, by a Genentech Foundation Fellowship of the Life Sciences Research Foundation.

New UC Santa Barbara center brings together research and teaching in biology, engineering and physical sciences.

Frank Doyle (left) and Samir Mitragotri, UC Santa Barbara

A new center at UC Santa Barbara has the development of an artificial pancreas in its sights, as well as new biomaterials, new tools for the detection and diagnosis of disease, and new mechanisms for drug delivery, among other cutting-edge scientific developments.

UC Santa Barbara’s new Center for BioEngineering (CBE), proposed by Frank Doyle, associate dean of research in the College of Engineering, was approved earlier this year by the Academic Senate. The center is a locus of research and teaching — at the interface of biology, engineering and physical sciences — that is already producing results that benefit industry and medicine. Research at the CBE is yielding important advances in the understanding, diagnosis, and treatment of common and devastating diseases such as cancer, diabetes, Alzheimer’s and macular degeneration.

CBE builds on UC Santa Barbara’s interdisciplinary strengths in biophysics, biomaterials, biomolecular discovery and systems biology, which allow for fundamental scientific discoveries to be transitioned to applications in medicine and biotechnology.

“UC Santa Barbara is very proud to be the home of the new Center for BioEngineering,” said Chancellor Henry T. Yang. “The creation of the CBE marks a major step forward for our campus. In this highly interdisciplinary field, UCSB is already at the forefront. Our new center will consolidate our position and support groundbreaking research aimed at finding innovative solutions for the diagnosis, treatment and prevention of disease.”

Samir Mitragotri, the founding director of the center and professor of chemical engineering, emphasizes the importance of CBE as a “home” for bioengineering on campus, since bioengineering is already an area of research in many of UC Santa Barbara’s centers, institutes, departments and colleges.

“I expect that the center will enable opportunities in terms of new fundamental understanding of disease mechanisms, and research at the interface of physical sciences, engineering sciences, medicine and biology,” said Mitragotri. “That includes understanding and development of new technologies to either diagnose or treat a disease.”

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UCLA research suggests importance of building up muscle mass.

Preethi Srikanthan, UCLA

UCLA researchers have been studying a condition called sarcopenic obesity, in which there is a low level of total body muscle mass combined with a high body mass index, or BMI, which is a measure for obesity. Endocrinologist Preethi Srikanthan explains that their goal was to see if this condition would correlate with higher insulin resistance and diabetes risk.

“We found that there was a positive association, which if you have sarcopenic obesity, you had a closer correlation between higher levels of insulin resistance and higher levels of glucose in general than a person with obesity alone,” Srikanthan said.

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UC Davis study suggests possible target for obesity, diabetes treatment.

Fu-Tong Liu, UC Davis

UC Davis Health System researchers have discovered that a protein called galectin-12 plays a key role in fat storage, a finding that could lead to improvements in treating obesity and diabetes. The researchers found that without the ability to make the protein, mice used in their research investigation stored 40 percent less body fat and had increased fat metabolism and decreased insulin resistance.

“This study for the first time demonstrates the importance of a galectin in energy metabolism,” said Fu-Tong Liu, distinguished professor and chair of the UC Davis Department of Dermatology and senior author on the paper.

The findings, published online this week in the early edition of the Proceedings of the National Academy of Sciences, point to galectin-12 as a potential target for the treatment of obesity and diabetes in humans. The breakdown and storage of fat in the body are both tightly controlled processes that involve numerous chemical signals, Liu said.

“In this case, galectin-12 seems to be signaling to fat cells that its time to conserve rather than burn energy,” he said. “If we can interrupt that signal, we have a chance at improving fat metabolism and reducing insulin resistance in patients with obesity and type 2 diabetes.”

Obesity is the No.1 predictor for the development of diabetes, a leading cause of death and disability in the United States. An estimated 24 million Americans have the disease. Between 90 and 95 percent of them have type 2 diabetes, and about 80 percent of people with type 2 diabetes are overweight or obese.

In its early stages, type 2 diabetes is characterized by insulin resistance. The pancreas is producing insulin, but for unknown reasons the body cannot use the insulin effectively. After several years, insulin production decreases, glucose builds up in the blood and the body cannot make efficient use of its main source of fuel. People with advanced diabetes may experience blindness, require limb amputations or suffer fatal organ failure.

In order to discover potential treatments for type 2 diabetes, Liu and his UC Davis colleagues have been working to understand the chemical signals involved in normal energy metabolism and storage. They isolated and cloned the galectin-12 gene 10 years ago. Since then, their studies have shown that the gene is preferentially expressed in fat cells, and that its expression is required for fat-cell differentiation. To enable a focus on specific biological mechanisms associated with galectin-12, the researchers worked with the UC Davis Mouse Biology Program to obtain genetically customized mice that have had individual genes systematically turned off or “knocked out.”

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UCLA study shows important factors for decreasing risk for type 2 diabetes.

Preethi Srikanthan, UCLA

Increasing your muscle mass is just as important as shedding body fat if you’re looking to lose weight and decrease your risk for type 2 diabetes. Those were the findings of a UCLA study led by endocrinologist Preethi Srikanthan.

“While it’s still important to measure fat mass loss and aim for weight loss, the maintenance and perhaps even increase of muscle mass is a very important part of therapy and this can be a very positive message because it’s hard to lose weight and as long as a person is able to get up, start moving, keep fit and build muscle mass, it may actually be a positive contributor to its metabolic abnormalities,” Srikanthan said.

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