UC Davis scientists target mitochondrial translocator protein.

Wenbing Deng, UC Davis

Working with lab mice models of multiple sclerosis (MS), UC Davis scientists have detected a novel molecular target for the design of drugs that could be safer and more effective than current FDA-approved medications against MS.

The findings of the research study, published online today in the journal EMBO Molecular Medicine could have therapeutic applications for MS as well as cerebral palsy and leukodystrophies, all disorders associated with loss of white matter, which is the brain tissue that carries information between nerve cells in the brain and the spinal cord.

The target, a protein referred to as mitochondrial translocator protein (TSPO), had been previously identified but not linked to MS, an autoimmune disease that strips the protective fatty coating off nerve fibers of the brain and spinal cord. The mitrochronical TSPO is located on the outer surface of mitochondria, cellular structures that supply energy to the cells. Damage to the fatty coating, or myelin, slows the transmission of the nerve signals that enable body movement as well as sensory and cognitive functioning.

The scientists identified mitochondrial TSPO as a potential therapeutic target when mice that had symptoms of MS improved after being treated with the anti-anxiety drug etifoxine, which interacts with mitochondrial TSPO. When etifoxine, a drug clinically available in Europe, was administered to the MS mice before they had clinical signs of disease, the severity of the disease was reduced when compared to the untreated lab animals. When treated at the peak of disease severity, the animals’ MS symptoms improved.

“Etifoxine has a novel protective effect against the loss of the sheath that insulates the nerve fibers that transmit the signals from brain cells,” said Wenbin Deng, principal investigator of the study and associate professor of biochemistry and molecular medicine at UC Davis.

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It could be the next pillar of medicine.

David Baylink (left), professor of medicine at Loma Linda University, asks a question during the bacterial therapeutics panel discussion at the Cell-Based Therapeutics symposium at UCSF, while Carl June (right), listens.

Old-line pharmaceutical companies and maturing biotech businesses both are graybeards compared to newer ventures focused on cell therapy.

With cell therapy the drugs are alive. Cells are engineered and reprogrammed outside the body to perform specific tasks – and then given as treatment.

“Cells are like soft robots,” said Wendell Lim, Ph.D., director of the Center for Systems & Synthetic Biology at UC San Francisco and an organizer of “Cell-Based Therapeutics: The Next Pillar of Medicine,” a daylong symposium held at UCSF’s Mission Bay campus last month.

Lim and other scientists aim to take advantage of the modules that already function within cells, and to manipulate them for specific therapeutic goals – sometimes by introducing new functions.

“We want to build therapeutic cells with precisely controlled activities,” Lim said. “We want to control how cells proliferate, where they go, how they are activated and how to turn them off or even destroy them when they are no longer needed.”

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Gender differences in meth addiction observed in adults may begin in adolescence.

Keith Heinzerling, UCLA

A UCLA-led study of adolescents receiving treatment for methamphetamine dependence has found that girls are more likely to continue using the drug during treatment than boys, suggesting that new approaches are needed for treating meth abuse among teen girls.

Results from the study, conducted by the UCLA Center for Behavioral and Addiction Medicine and the community-based substance abuse treatment program Behavioral Health Services Inc., are published in the April edition of the Journal of Adolescent Health.

“The greater severity of methamphetamine problems in adolescent girls compared to boys, combined with results of studies in adults that also found women to be more susceptible to methamphetamine than men, suggests that the gender differences in methamphetamine addiction observed in adults may actually begin in adolescence,” said the study’s lead author, Dr. Keith Heinzerling, a health sciences assistant clinical professor of family medicine at the David Geffen School of Medicine at UCLA.

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Bleeding, transfusion, readmission, death more likely after taking SSRIs.

Andrew Auerbach, UC San Francisco

Selective serotonin reuptake inhibitors (SSRIs) – among the most widely prescribed antidepressant medications – are associated with increased risk of bleeding, transfusion, hospital readmission and death when taken around the time of surgery, according to a new analysis.

Researchers from UC San Francisco and Baystate Medical Center in Massachusetts looked at the medical records of more than 530,000 patients who underwent surgery at 375 U.S. hospitals between 2006 and 2008. Their results were published today (April 29) in JAMA Internal Medicine.

“There have been small studies that suggested there was a problem, but it has never been well-proven,” said lead author Andrew D. Auerbach, M.D., M.P.H., a UCSF professor of medicine. “With this huge data set, we feel confident in saying that SSRIs are associated with about a 10 percent increased risk for these adverse outcomes.”

The study authors noted that patients on SSRIs are more likely to have conditions that in themselves increase surgical risk, such as obesity, chronic pulmonary disease and depression.

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Discover could help in development of drugs to fight diseases.

Shengben Li (left) is a postdoctoral researcher in the lab of Xuemei Chen at UC Riverside.

RNA molecules, made from DNA, are best known for their role in protein production. MicroRNAs (miRNAs), however, are short (~22) nucleotide RNA sequences found in plants and animals that do not encode proteins but act in gene regulation and, in the process, impact almost all biological processes — from development to physiology to stress response.

Present in almost in every cell, microRNAs are known to target tens to hundreds of genes each and to be able to repress, or “silence,” their expression.  What is less well understood is how exactly miRNAs repress target gene expression.

Now a team of scientists led by geneticists at the University of California, Riverside has conducted a study on plants (Arabidopsis) that shows that the site of action of the repression of target gene expression occurs on the endoplasmic reticulum (ER), a cellular organelle that is an interconnected network of membranes — essentially, flattened sacs and branching tubules — that extends like a flat balloon throughout the cytoplasm in plant and animal cells.

“Our study is the first to demonstrate that the ER is where miRNA-mediated translation repression occurs,” said lead researcher Xuemei Chen, a professor of plant cell and molecular biology and a Howard Hughes Medical Institute-Gordon and Betty Moore Foundation investigator. “To understand how microRNAs repress target gene expression, we first need to know where microRNAs act in the cell.  Until now no one knew that membranes are essential for microRNA activity.  Our work shows that an integral membrane protein, AMP1, is required for the miRNA-mediated target gene repression to be successful.  As AMP1 has counterparts in animals, our findings in plants could have broader implications.”

Study results appear today in the journal Cell.

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UCLA researchers will lead network of U.S. academic centers to explore experimental drugs.

James McCracken, UCLA

UCLA has been awarded a $9 million contract by the National Institute of Mental Health for an ambitious effort to rapidly study promising new drugs that may help restore normal development and brain function in children with autism spectrum disorders.

UCLA researchers will create and lead a network of U.S. academic centers that will carry out early “high risk/high reward” studies of experimental medications over a three-year period. The goal of the project, New Experimental Medicine Studies: Fast–Fail Trials in Autism Spectrum Disorders, is to determine within weeks rather than years (“fast”) if a particular pharmacological compound is working or not (“fail”).

Recent progress in identifying the genes and biological components involved in autism spectrum disorders (ASD) holds great promise for the identification of life-changing treatments for individuals of all ages, said the project’s principal investigator, Dr. James McCracken, a professor of psychiatry and director of the division of child and adolescent psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA.

“Current medical treatments are commonly prescribed by physicians for ASD but only to manage difficult behaviors, like aggressiveness, hyperactivity and self-injury,” McCracken said. “Such treatments can be important and helpful, but they do not impact the core problems of the disorders.

“This is definitely the most exciting time yet to be involved in treatment research for ASD,” he added. “Our basic science colleagues are generating enormous information on the likely underlying causes of this common and often disabling condition. We are well positioned to apply the basic science and find drugs that make a difference.”

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UCLA study shows versatility of nanodiamond as targeted drug-delivery agent to tumor site.

Nanodiamonds bound to the chemotherapy drug epirubicin are enclosed within a lipid membrane and coupled to antibodies specific to hard-to-treat tumors. These hybrid drug delivery agents cause tumors to regress in size while markedly improving drug tolerance.

Recently, doctors have begun to categorize breast cancers into four main groups according to the genetic makeup of the cancer cells. Which category a cancer falls into generally determines the best method of treatment.

But cancers in one of the four groups — called “basal-like” or “triple-negative” breast cancer (TNBC) — have been particularly tricky to treat because they usually don’t respond to the “receptor-targeted” treatments that are often effective in treating other types of breast cancer. TNBC tends to be more aggressive than the other types and more likely to recur, and can also have a higher mortality rate.

Fortunately, better drug therapies may be on the horizon. UCLA researchers and collaborators led by Dean Ho, a professor at the UCLA School of Dentistry and co-director of the school’s Jane and Jerry Weintraub Center for Reconstructive Biotechnology, have developed a potentially more effective treatment for TNBC that uses nanoscale, diamond-like particles called nanodiamonds.

Nanodiamonds are between 4 and 6 nanometers in diameter and are shaped like tiny soccer balls. Byproducts of conventional mining and refining operations, the particles can form clusters following drug binding and have the ability to precisely deliver cancer drugs to tumors, significantly improving the drugs’ desired effect. In the UCLA study, the nanodiamond delivery system has been able to home in on tumor masses in mice with triple negative breast cancer.

Findings from the study are published online today (April 15) in the peer-reviewed journal Advanced Materials.

“This study demonstrates the versatility of the nanodiamond as a targeted drug-delivery agent to a tumor site,” said Ho, who is also a member of the California NanoSystems Institute at UCLA, UCLA’s Jonsson Comprehensive Cancer Center and the UCLA Department of Bioengineering. “The agent we’ve developed reduces the toxic side effects that are associated with treatment and mediates significant reductions in tumor size.”

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Phase three study initiated.

Richard Finn, UCLA

An experimental drug being investigated for the treatment of advanced breast cancer by researchers from the Revlon/UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center this week received breakthrough therapy designation from the U.S. Food and Drug Administration.

In a clinical trial, patients with advanced breast cancer that was estrogen-receptor positive (ER+) and HER2-negative (HER2-), and who were given palbociclib (PD 0332991, Pfizer Inc.) in addition to the standard anti-estrogen treatment of letrozole had significantly higher progression-free survival — the length of time a patient is on treatment without tumor growth — than patients taking letrozole alone.

Enacted as part of the 2012 FDA Safety and Innovation Act, the breakthrough therapy designation was created by the agency to expedite the development and review of a potential new medicine if it is “intended, alone or in combination with one or more other drugs, to treat a serious of life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.”

Dr. Richard S. Finn, associate professor of medicine at the Jonsson Cancer Center, initially reported the phase two clinical data supporting the designation in December 2012 at the CTRC-AACR San Antonio Breast Cancer Symposium. The clinical study was built on laboratory work from the Translational Oncology Research Laboratory directed by Dr. Dennis Slamon, professor of medicine at UCLA and director of the Jonsson Cancer Center’s Revlon/UCLA Women’s Cancer Research Program.

In preclinical work, palbociclib was tested in a panel of human breast cancer cells growing in culture dishes and showed very encouraging activity, specifically against ER+ cancer cells. These preclinical observations were then moved into phase 1 clinical studies. Led by Finn and Slamon at UCLA, the studies were designed to determine the doses and safety of a combination with letrozole, a commonly used drug for ER+ breast cancer.

Once the phase 1 studies were completed, the phase two studies were performed in 165 patients with breast cancer with ER+ disease. The drug was designated as a breakthrough therapy by the FDA based on the preliminary analysis of the phase 2 data showing that the median progression-free survival of patients given the palbociclib-letrozole combination was 26.1 months, compared with 7.5 months for those given letrozole alone. Among patients with measurable disease, 45 percent receiving the combination had confirmed responses, compared with 31 percent for letrozole alone, and the clinical benefit rates (tumor shrinkage and/or stable disease for a minimum of six months) were 70 percent for those receiving the combination therapy, versus 44 percent for letrozole only.

“This drug combination demonstrated a dramatic and clinically meaningful effect on progression-free survival in women with ER+ breast cancer,” Finn said. “These results confirm the preclinical work we began at the Translational Lab.”

Finn and colleagues have initiated a randomized, multicenter, double-blind phase three study to evaluate palbociclib combined with letrozole, compared with letrozole alone, as a first-line treatment for post-menopausal patients with ER+, HER2-, locally advanced or metastatic breast cancer. The researchers will continue to work closely with Pfizer and the FDA to better understand the implications of the breakthrough therapy designation with the hope that further study will support potential regulatory submission.

Slamon said the phase two study results validate the Translational Laboratory’s approach.

“By identifying the correct targets for treatment in the right patient population, we move forward with personalized oncology that we hope will greatly improve the outcomes for this group of breast cancer patients,” he said. “These results are as exciting as the initial results we saw for trastuzumab (Herceptin) in HER2+ breast cancers but represent a new approach for a different and larger subset of breast cancers, namely those that are ER+.”

Slamon said the researchers are working diligently to enroll the phase three validation study as quickly and safely as possible.

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Results of UCSF clinical trial may change standard of care for primary CNS lymphoma.

James Rubenstein, UC San Francisco

A phase two clinical trial testing a new protocol for treating a relatively rare form of brain cancer, primary CNS lymphoma, may change the standard of care for this disease, according to doctors at UC San Francisco who led the research.

Described this week in the Journal of Clinical Oncology, the trial involved 44 patients who were given a combination of high-dose chemotherapy with immune therapy, rather than the standard combination of chemotherapy with a technique known as whole-brain radiotherapy.

The new treatment approach was significantly less toxic because it avoided whole-brain radiotherapy, which at high doses can kill brain cells and lead to a progressive deterioration of the function of the nervous system in patients. Many patients die from the toxicity of the radiation as opposed to the cancer itself.

The new treatment also seemed to work better, with the majority of patients on the trial still alive with a follow-up of nearly five years, researchers found.

The lymphoma-free survival of patients with this form of brain cancer was doubled compared to the lymphoma-free survival in previous multicenter U.S. cooperative-group-sponsored clinical trials involving brain radiotherapy, said UCSF oncologist James Rubenstein, M.D., Ph.D., associate professor of medicine, who led the study.

In addition, unlike previous treatments for primary CNS lymphoma, the new approach was equally effective in older patients – those over 60 – as it was in younger patients. This is particularly significant given that the incidence of this type of brain tumor appears to be increasing in patients 65 and older.

Rubenstein is a member of the UCSF Helen Diller Family Comprehensive Cancer Center, which is one of the country’s leading research and clinical care centers, and is the only comprehensive cancer center in the San Francisco Bay Area.

The work raises the possibility of taking a “personalized medicine” approach to guiding treatment for this form of cancer because the researchers identified a biomarker – a gene called BCL6 – which could predict the outcome of treatment depending on how much of the gene was present in the tumor.

A randomized clinical trial, which will test the effectiveness of the new therapeutic approach in a larger patient population, is now enrolling at UCSF and at other medical centers in the United States.

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Brain stimulation in rats suggests new, unconventional therapy.

Cortical nuerons. Image courtesy of NIH/A. Bonci

By stimulating one part of the brain with laser light, researchers at the National Institutes of Health (NIH) and the Ernest Gallo Clinic and Research Center at UC San Francisco (UCSF) have shown that they can wipe away addictive behavior in rats – or conversely turn non-addicted rats into compulsive cocaine seekers.

“When we turn on a laser light in the prelimbic region of the prefrontal cortex, the compulsive cocaine seeking is gone,” said Antonello Bonci, MD, scientific director of the intramural research program at the NIH’s National Institute on Drug Abuse (NIDA), where the work was done. Bonci is also an adjunct professor of neurology at UCSF and an adjunct professor at Johns Hopkins University.

Described this week in the journal Nature, the new study demonstrates the central role the prefrontal cortex plays in compulsive cocaine addiction. It also suggests a new therapy that could be tested immediately in humans, said Billy Chen of NIDA, the lead author of the study.

Any new human therapy would not be based on using lasers, but would most likely rely on electromagnetic stimulation outside the scalp, in particular a technique called transcranial magnetic stimulation (TMS). Clinical trials are now being designed to test whether this approach works, Chen added.

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UC Davis MIND Institute director to lead project.

Leonard Abbeduto, UC Davis

A team of researchers led by UC Davis MIND Institute Director Leonard Abbeduto will investigate the effectiveness of testing procedures to examine the spoken language development of people with fragile X syndrome and people with Down syndrome, through a new five-year, $3 million grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.

The grant will be used to determine whether these procedures can be utilized to gauge the efficacy of new drugs under development for treating the cognitive and behavioral challenges that face individuals with intellectual disabilities, including fragile X syndrome and Down syndrome.

“Language improvement is an important target for many of these promising new drugs,” Abbeduto said. ”However, we don’t yet have tools sensitive and accurate enough to measure change in language in clinical trials. This study may lead us to understand the efficacy of these drugs.”

Fragile X syndrome is the most common inherited cause of intellectual disability and ranges in severity from learning disabilities to more severe cognitive impairment. It is the most common single-gene cause of intellectual disability and of autism spectrum disorder. Down syndrome, also known as trisomy 21, is a chromosomal condition caused by the presence of all or part of a third copy of chromosome 21. It is the leading genetic cause of intellectual disability. Down syndrome is accompanied by distinctive facial characteristics and also can be accompanied by other medical conditions, including congenital heart defects.

The research conducted in Abbeduto’s lab has focused, in part, on identifying the specific profiles of language development that characterize fragile X syndrome and Down syndrome, including the aspects of language that are similar or differ between these two disorders.

For the current study, Abbeduto will collaborate with researchers at Rush University Medical Center in Chicago, Emory University School of Medicine in Atlanta, the University of Wisconsin, Madison and the University of Arizona, Tucson. The study will evaluate the reliability and sensitivity of a language-evaluation procedure that Abbeduto has pioneered for two decades called expressive-language sampling.

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The abnormalities may be associated with increased risk of neuroendocrine tumors.

Peter Butler, UCLA

Individuals who had taken a type of drug commonly used to treat Type 2 diabetes showed abnormalities in the pancreas, including cell proliferation, that may be associated with an increased risk of neuroendocrine tumors, according to a new study by researchers from UCLA and the University of Florida. Their findings were published online March 22 in the journal Diabetes.

The researchers, from the Larry L. Hillblom Islet Research Center at UCLA and the Diabetes Center at the University of Florida, found that cell mass was increased approximately 40 percent in the pancreases of deceased organ donors who had Type 2 diabetes and who had been treated with incretin therapy. This widely used type of treatment takes advantage of the action of a gut hormone known as glucagon-like peptide 1 (GLP-1) to lower blood sugar in the body.

Although there have been conflicting reports on the effects of the incretin class of drugs on the pancreas in animal studies, this is the first study to note such changes in the human pancreas. The research was made possible by a unique research consortium called nPOD (Network for Pancreatic Organ Donors with Diabetes), led by Dr. Mark Atkinson, a professor of pathology and pediatrics at the University of Florida. The network, which is funded by the Juvenile Diabetes Research Foundation, obtains pancreases from deceased organ donors, with permission of their next of kin, to better understand diabetes by investigating tissues of those with the disease.

“There is an increasing appreciation that animal studies do not always predict findings in humans,” said Dr. Peter Butler, director of UCLA’s Hillblom Islet Research Center and chief of the endocrinology, diabetes and hypertension unit. “The nPOD program is therefore a very precious resource.”

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