UC Irvine-led study points to role endocannabinoids play in energy metabolism.

Daniele Piomelli, UC Irvine

Stop exercising, eat as much as you want … and still lose weight? It sounds impossible, but UC Irvine and Italian researchers have found that by blocking a natural, marijuana-like chemical regulating energy metabolism, this can happen, at least in the lab.

To create this hypermetabolic state, UC Irvine pharmacology professor Daniele Piomelli and colleagues engineered neurons in the forebrains of mice to limit production of an endocannabinoid compound called 2-AG. All mammalian brains contain 2-AG, which the researchers believe helps control the activity of forebrain neural circuits involved in energy dissipation.

As a result, these modified mice ate more and moved less than typical mice but did not gain any weight, even when they were fed a high-fat diet. Additionally, they did not develop any signs of metabolic syndrome, a combination of health problems such as obesity and high blood pressure that increases the risk of cardiovascular disease and diabetes.

“We discovered that these mice were resistant to obesity because they burned fat calories much more efficiently than normal mice do,” said Piomelli, the Louise Turner Arnold Chair in the Neurosciences. “We had known that endocannabinoids play a critical role in cell energy regulation, but this is the first time we found a target where this occurs.”

Specifically, these mutant mice stayed thin because their brown fat — a type of fat that exists in all mammals to keep them warm — became hyperactive and was converted into heat at a much more rapid pace than in ordinary mice.

Does this mean that a drug limiting 2-AG levels may one day become a weight-loss panacea? That’s more easily said than done, according to Piomelli. For the study, the mice were bred with brain cells manipulated to limit 2-AG production — which can’t be done with humans.

“To produce the desired effects, we would need to create a drug that blocks 2-AG production in the brain, something we’re not yet able to do,” he explained. “So don’t cancel that gym membership just yet. But as you hit the treadmill, think about the added health benefits if you could train your brain to make fewer endocannabinoids.”

Endocannabinoid compounds are created naturally in the body and share a similar chemical structure with THC, the primary psychoactive component of the marijuana plant, Cannabis. Endocannabinoids are distinctive because they link with protein molecule receptors — called cannabinoid receptors — on the surface of cells. For instance, when a person smokes marijuana, the cannabinoid THC activates these receptors. Because the body’s natural cannabinoids control a variety of factors, such as pain, mood and appetite, they’re attractive targets for drug discovery and development. Piomelli is one of the world’s leading endocannabinoid researchers. His groundbreaking work is showing that this system can be exploited by new treatments to combat anxiety, pain, depression and obesity.

Findings appear in the March issue of Cell Metabolism. Nicholas DiPatrizio, Giuseppe Astarita, Kwang-Mook Jung, Jason Clapper, Ana Guijarro, Dean Thongkham and Agnesa Avanesian of UC Irvine; Giuseppe D’Agostino and Sabrina Diano of Yale University; and Andrea Frontini and Saverio Cinti of Marche Polytechnic University in Ancona, Italy, contributed to the study, which received support from the National Institute on Drug Abuse.

About the University of California, Irvine: Founded in 1965, UC Irvine is a top-ranked university dedicated to research, scholarship and community service. Led by Chancellor Michael Drake since 2005, UC Irvine is among the most dynamic campuses in the University of California system, with nearly 28,000 undergraduate and graduate students, 1,100 faculty and 9,000 staff. Orange County’s second-largest employer, UC Irvine contributes an annual economic impact of $4 billion. For more news, visit www.today.uci.edu.

Iraq, Afghanistan veterans with pain, PTSD prescribed more opiates than other veterans with pain.

Karen Seal

Veterans of Iraq and Afghanistan with post-traumatic stress disorder (PTSD) and other mental health diagnoses were significantly more likely to be prescribed opiates for pain than other veterans with pain, according to a study led by researchers at the San Francisco VA Medical Center (SFVAMC) and the University of California, San Francisco.

The veterans with pain and PTSD who received opiates were significantly more likely to receive higher dose prescriptions, two or more opiate prescriptions and concurrent prescriptions of sedative-hypnotics such as valium. They also were more likely to request early refills.

In addition, all veterans who were prescribed opiates were also at significantly higher risk of serious adverse clinical outcomes, such as drug and alcohol-related overdoses, suicide and violent injury, with the risk being most pronounced for veterans with PTSD.

To address the issue, the study authors recommend that the VA implement more broadly its current program of what lead author Karen Seal, M.D., M.P.H., a physician at SFVAMC, called a “multifaceted, integrated approach” to simultaneously managing pain and PTSD.

Seal, an associate professor in residence of medicine and psychiatry at UCSF, noted that because of improved body armor and better war zone medical care, more Iraq and Afghanistan veterans have survived wounds that would have been fatal in earlier conflicts. “Many of these veterans with severe chronic pain also have PTSD as a result of the same trauma that caused their physical injuries,” she said.

The study of 141,029 veterans who served in Iraq and Afghanistan from 2005 through 2010 appears in the March 7 issue of the Journal of the American Medical Association.

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Mechanism causes melanoma to over-produce protein targeted by the drug.

Roger Lo, UCLA

Cancer is tough to kill and has many ways of evading the drugs used by oncologists to eliminate it.

Now, researchers at UCLA‘s Jonsson Comprehensive Cancer Center have uncovered how an advanced form of melanoma gets around an inhibitor called Zelboraf, which targets the mutated BRAF gene.

By examining the part of the melanoma genome that encodes proteins, called the exome, Jonsson Cancer Center scientists discovered that in some patients with BRAF-mutated metastatic melanoma, the mutated BRAF gene driving the cancer becomes amplified as the cancer develops resistance to an inhibitor.

Quite simply, by increasing the copies of the mutated BRAF gene, the melanoma is trying to over-produce the protein targeted by the drug, essentially outnumbering the inhibitor. The study findings may lead to alternative ways of preventing or treating resistant melanomas.

“Understanding and solving the problem of how cancer gets around targeted drugs is arguably one of the highest priorities in modern-day cancer medicine,” said the study’s senior author, Dr. Roger Lo, an assistant professor of dermatology and of molecular and medical pharmacology and a Jonsson Cancer Center scientist. “In this study, we found that in some patients, the cancer simply makes more of the target, the mutated BRAF gene, so that the drug dose becomes too weak to fight the cancer.

“If you think of the mutation as a right hand and the BRAF inhibitor as a left hand and the two clasp to be effective, there’s clearly an optimal ratio to ensure the mutated gene is fully inhibited. Here, we get more of the drug target, which has the same effect as dropping the drug level.”

The one-year study is published today (March 6) in the peer-reviewed journal Nature Communications.

About 50 percent of patients with metastatic melanoma, roughly 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf, two pills taken twice a day. Zelboraf was approved by the U.S. Food and Drug Administration for use in metastatic melanoma in August 2011. Many other common human cancers, including cancers of the colon, thyroid and lung, also harbor BRAF-mutated subsets, Lo said.

Oncologists cannot give more Zelboraf to these patients to combat the increased number of mutated BRAF genes because the dose approved by the FDA is the maximum tolerated dose, Lo said. However, Zelboraf could perhaps be given with inhibitors of other cell-signaling pathways in metastatic melanoma to try to stop patients from becoming resistant.

Lo and his team examined samples from 20 patients for this study, taking their normal tissue, their tumor tissue before treatment with Zelboraf, and a tissue sample when the cancer had responded earlier but subsequently became resistant. Using high-throughput DNA sequencing technology, the scientists examined the entire cancer exome to see what changes were occurring that may point to resistant mechanisms.

Lo found that five of the 20 patients showed increased copies of the mutated BRAF gene. Cell lines developed from melanoma patients also showed pathways downstream of the amplified gene that could be blocked with inhibitors to fight resistance.

“For the first time, we were able to see in actual patient tissue samples how the cancer gets around this drug by altering the target,” Lo said. “It appears that the drug target is not only mutated and hyper-activated, but it’s also massively over-produced in some cases of clinical relapse.”

Lo said there’s an experimental drug that also inhibits mutated BRAF which may be effective against this form of melanoma at a dose that does not result in substantial side effects. In that case, an oncologist might have room to increase the drug dose once a relapse driven by BRAF amplification is encountered in the clinic.

Scientists so far have discovered five mechanisms of BRAF-inhibitor resistance in melanoma patients, accounting for about 60 to70 percent of patients. However, 30 to 40 percent of patients are relapsing by as-yet uncovered mechanisms.

Going forward, Lo and his team will seek to find out what is happening molecularly in every patient that relapses after therapy so that novel combination drug strategies can be developed to help them.

“If we know what happens in every relapse, we can have a plan in place that will help us avoid or overcome resistance,” he said.

About 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease.

The study was funded by a Bud and Sue Selig Innovative Research Grant from Stand Up to Cancer, the Burroughs Wellcome Fund, the Seaver Institute, and the Richard C. Seaver Charitable Trust. Additional support came from the National Cancer Institute, the V Foundation for Cancer Research, the Melanoma Research Foundation, the Melanoma Research Alliance, the American Skin Association, the Caltech-UCLA Joint Center for Translational Medicine, the Sidney Kimmel Foundation for Cancer Research, Wendy and Ken Ruby, and Louis Belley and Richard Schnarr.

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 11 of the last 12 years.

Silencing it impairs tumor growth, making ROR1 a potential therapeutic target.

Thomas Kipps, UC San Diego

A team of scientists at the University of California, San Diego, Moores Cancer Center has identified a novel protein expressed by breast cancer cells — but not normal adult tissues — that could provide a new target for future anti-cancer drugs and treatments.

Led by Thomas J. Kipps, M.D., Ph.D., Evelyn and Edwin Tasch Chair in Cancer Research and interim director of the UC San Diego Moores Cancer Center, the scientists found that the tumor cells of patients with breast cancer frequently express the Receptor-tyrosine-kinase-like Orphan Receptor 1, or ROR1. They found that silencing expression of ROR1 impaired the growth and survival of human breast cancer cells. The findings are published in today’s (March 5) online issue of PLoS One.

ROR1 was first identified in the early 1990s and labeled an orphan receptor because its purpose was unknown. Subsequent work found that ROR1 is expressed at high levels during embryogenesis, during which time it plays an important role in regulating embryonic muscle and skeletal development. During fetal development, however, the expression of this protein is turned off. Normal cells and tissues in adults do not typically express ROR1.

Cancer cells, however, are a different matter.

“Cancer cells tend to acquire features of less differentiated cells,” said Kipps, interim director of the UC San Diego Moores Cancer Center and a professor of medicine in the UC San Diego School of Medicine. “They often can be found to have features of embryonic cells.”

In recent years, Kipps and others have become increasingly interested in the role of ROR1 plays in the growth of cancer — and whether the protein might provide new options for stopping development of the disease. In 2008, for example, Kipps and colleagues reported that patients with leukemia treated with whole-cell vaccines could generate antibodies that reacted with their leukemia cells and the leukemia cells of other patients, but not with normal cells. They identified that such antibodies could target ROR1, accounting for the specificity of these antibodies in reacting with cancer cells. They identified another protein that could interact with ROR1 to stimulate the growth and/or survival of leukemia cells and that antibodies generated against ROR1 could block this function.

The discovery that ROR1 functions similarly in breast cancer heightens hopes. When the protein was silenced in human breast cancer cells, the cancer cells had slower rates of growth in the laboratory and in animal studies.

“There was a qualitative difference,” said Kipps. “When ROR1 was knocked down, it took away some of the growth advantage enjoyed by cancer cells. Their capacity to survive also was impaired. This could affect the capacity of the cancer cells to survive treatment with other anti-cancer agents or generate tumors altogether.”

The researchers report that expression levels of ROR1 correlate with the severity of at least some forms of breast cancer. The most aggressive cancers were the ones more likely to express ROR1. “That suggests ROR1 could be a good target for treating the most aggressive kinds of breast cancer, particularly the ones that lack expression of hormone receptors or the marker HER2/neu, which already can be targeted by monoclonal antibodies,” Kipps said.

The discovery of ROR1′s role in both blood and breast cancers also suggests it might have a similar function in other forms of cancer, a possibility Kipps said researchers will pursue.

Funding for this research came, in part, from the National Institutes of Health and the Leukemia and Lymphoma Society of America.

Co-authors of the paper are Suping Zhang, Liguang Chen, Bing Cui, Han-Yu Chuang, Jianqiang Yu, Jessica Wang-Rodriguez, Li Tang, George Chen and Grzegorz W. Basak, all at the UC San Diego Moores Cancer Center.

The article can be found online at http://dx.plos.org/10.1371/journal.pone.0031127

UCSF-led study shows how interferon works to suppress virus in patients with HIV, hepatitis.

Satish Pillai, UC San Francisco

A drug once taken by people with HIV/AIDS, but long ago shelved after newer, modern antiretroviral therapies became available, has now shed light on how the human body uses its natural immunity to fight the virus — work that could help uncover new targets for drugs.

In an article published online this month by the journal PNAS, a group of American and Swiss researchers led by scientists at the University of California, San Francisco, presented the first clinical assessment of how this drug fights infections in people. The drug, called interferon, is a biotechnology product based on a protein the body naturally produces to fight infections.

While purified interferon was given to people with HIV/AIDS in the early days of the epidemic because it alleviated many of the symptoms of the disease, its mode of action was always something of a black box.

“Nobody knew how it worked,” said Satish K. Pillai, Ph.D., lead investigator and an assistant professor of Medicine at UCSF and the UCSF-affiliated San Francisco VA Medical Center.

Experiments in the laboratory in recent years have shown how interferon may work to suppress HIV in vitro, but there was no clinical evidence until now showing how the drug attacks HIV in treated patients. The problem is that so few people actually take interferon for HIV any more. However, interferon is still used in combination with other drugs to treat hepatitis C, which gave the team the possibility to assess its effect on HIV.

Interferon is commonly used to treat people with hepatitis C virus, and Pillai and his colleagues were able to identify 20 people enrolled in the Swiss HIV Cohort Study, which began in 1988, who have both HIV and hepatitis C. All 20 were taking interferon to treat their hepatitis C, but none were receiving antiretroviral drugs to treat HIV. This allowed researchers to examine how interferon works to suppress the virus.

How interferon works

The new work sheds further light on somewhat mysterious components of the immune system known as restriction factors, which are chemicals the human body produces to keep viruses like HIV in check and prevent them from infecting other cells.

These are just two fronts in the overall battle between HIV and the immune system — a battle in which the immune system seeks to destroy the virus while the virus constantly counters by undermining the immune system.

Unlike other parts of the immune system, where whole cells gobble up invading pathogens or attack other cells, the action of these restriction factors is more subtle and localized within the infected cell itself — one of the reasons scientists didn’t appreciate what they do until just a few years ago.

One of them, called APOBEC3, fights viruses by stealthily jumping onto new virus particles as they form. Therein, the APOBEC3 protein fouls up HIV’s genetic material by mutating it. When the virus tries to infect another cell, it no longer has the potency to replicate.

Another factor, called tetherin, takes an even more direct approach. It attaches to virus particles as they emerge from infected cells in the body and literally tethers them in place, preventing them from moving elsewhere in the body where they could infect new cells.

HIV has its own countermeasures to thwart these defenses. It produces a protein known as Vpu that neutralizes tetherin. Another HIV protein, called Vif, subverts APOBEC.

In the new study, Pillai and his colleagues showed that interferon combats HIV by mediating the action of both of these restriction factors. They collected samples from the 20 patients and measured the levels of APOBEC3 and tetherin before, during and after they took the drug interferon. The levels increased in response to interferon when the drug was in the bloodstream, and patients with the highest restriction factor levels showed the most precipitous drop in HIV viral load during interferon treatment.

While this insight does not immediately suggest new drugs or new ways of treating people with HIV, Pillai said scientists armed with this knowledge may one day figure out how to enhance this defense mechanism and specifically enhance the expression of restriction factors like tetherin and APOBEC3 in HIV-1–infected individuals.

If these factors can be induced to higher levels, their attack on the virus may become more potent — perhaps even overriding HIV’s countermeasures and helping flush the virus from infected cells.

The article, “Role of retroviral restriction factors in the interferon-α–mediated suppression of HIV-1 in vivo,” was written by Satish K. Pillai, Mohamed Abdel-Mohsen, John Guatelli, Mark Skasko, Alexander Monto, Katsuya Fujimoto, Steven Yukl, Warner C. Greene, Helen Kovari, Andri Rauch, Jacques Fellay, Manuel Battegay, Bernard Hirschel, Andrea Witteck, Enos Bernasconi, Bruno Ledergerber, Huldrych F. Günthard, Joseph K. Wong, and the Swiss HIV Cohort Study.

In addition to UCSF, the authors of this study are affiliated with the San Francisco VA Medical Center, the Veterans Affairs San Diego Healthcare System at the University of California at San Diego, the Gladstone Institute of Virology and Immunology, and the Swiss university hospitals of Zurich, Berne, Lausanne, Basel, Geneva, St. Gallen and Lugano.

This work was funded by the National Institutes of Health and through the American Recovery and Reinvestment Act. Additional support was provided by Swiss HIV Cohort Study Project 594; the Veterans Affairs Merit Review; and several Swiss National Science Foundation Grants. The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation and the Swiss HIV Cohort Study Research Foundation.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

UCSF research shows one-two punch blocks tumor growth, invasion and metastasis in mice.

Donald McDonald, UC San Francisco

Simultaneous targeting of two different molecules in cancer is an effective way to shrink tumors, block invasion, and stop metastasis, scientists at the University of California, San Francisco, have found — work that may improve the effectiveness of combination treatments that include drugs like Avastin.

The two-target approach, tested in mice with a type of cancer known as neuroendocrine pancreatic tumors, may have broad application for treating a wide variety of cancers, the UCSF team said. The drugs used in the tests belong to classes of pharmaceuticals that are either on the market or under development in clinical trials.

Clinical trials also are already under way to gauge effectiveness of the approach in humans with prostate cancer, breast cancer, and other tumor types. The UCSF study, described in the journal Cancer Discovery this week, is the first to show how the drug combination works in the laboratory.

The results are promising, said Donald McDonald, M.D., Ph.D., a member of the UCSF Helen Diller Family Comprehensive Cancer Center and the Cardiovascular Research Institute and professor of anatomy, who led the research.

In the study, treating mice with the dual-target approach turned aggressive tumors with invasive fingers penetrating surrounding tissues and many metastases into tiny balls with few or no metastases.

“It’s the combination of approaches — there’s a synergy between the two,” McDonald said. “You add two and two, and you get 10.”

Target proteins play role in malignant tumors

The two targets are both proteins that scientists have known for years are involved in cancer. Both play important roles in malignant tumors.

The first, called c-MET, is involved in two processes associated with the most deadly cancers. A clinical marker of cancer aggressiveness, c-MET drives tumor invasion into surrounding tissues. It is also involved in metastasis — the spread of cancer cells to other parts of the body where they can establish new tumors.

The second target is a protein known as vascular endothelial cell growth factor (VEGF). VEGF is a protein that promotes the growth of new blood vessels. Growing tumors hijack this process to expand their network of blood vessels to provide nutrients. Drugs blocking VEGF have been developed based on the simple assumption that tumors cannot grow if you choke off their blood supply.

Drugs that target these molecules are in development, and a few are already on the market. The U.S. Food and Drug Administration (FDA) approved the first of these in 2004 to treat metastatic colon cancer. That drug, called Avastin, is manufactured by the South San Francisco-based company Genentech. Avastin was approved for metastatic breast cancer in 2008 under the FDA’s accelerated approval program.

The FDA revoked approval of Avastin for breast cancer last year after further assessing the relative risks and benefits to women taking it. Blocking VEGF seemed to slow tumor growth for awhile, but the FDA determined that it did not significantly improve or extend the lives of most women taking it.

“It was not clear why some tumors responded and others did not. It was also unclear why some tumors would respond initially and then would stop responding,” said McDonald, who has studied blood vessels in tumors and the effect of cancer drugs for years in his UCSF laboratory.

Two years ago former UCSF professor Douglas Hanahan and colleagues found in laboratory experiments that Avastin-like drugs would shrink tumors but unexpectedly did something else as well. The drugs also morphed tumors from roundish blobs into highly irregular growths with tendrils that penetrated surrounding tissues and even spread to other organs — suggesting that the VEGF blockade could also make tumors more aggressive, invasive and metastatic.

McDonald’s group confirmed Hanahan’s findings and discovered that c-MET was involved. In their latest research, Barbara Sennino, PhD, with other investigators in his group set out to determine whether c-MET drove tumor aggressiveness during anti-VEGF therapy. What their paper shows is that blocking c-MET and VEGF together in mice is more powerful than blocking either alone because it not only slows tumor growth but also reduces invasion and metastasis.

They tested two inhibitors of VEGF—a neutralizing antibody and sunitinib — and three inhibitors of c-MET — crizotinib, PF-04217903, and cabozantinib (XL184). Unlike the other agents, cabozantinib simultaneously inhibits both c-MET and VEGF. Inhibition of c-MET and VEGF together with a drug combination or with cabozantinib had more profound effects on tumors than any of the agents that blocked only one of the targets.

These promising laboratory results still need more tests of safety and effectiveness in the clinic, McDonald said, and it may be a year or more before the drugs are routinely available to patients.

The article, “Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors” by Barbara Sennino, Toshina Ishiguro-Oonuma, Ying Wei, Ryan M. Naylor, Casey W. Williamson, Vikash Bhagwandin, Sebastien P. Tabruyn, Weon-Kyoo You, Harold A. Chapman, James G. Christensen, Dana T. Aftab, and Donald M. McDonald appears in the March 1 issue of Cancer Discovery.

None of the UCSF authors has any financial interest in the companies that make the drugs used in the experiments, which also involved scientists at Pfizer and Exelixis.  The work was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, both components of the National Institutes of Health. Additional support was provided by the companies Pfizer and Exelixis and by AngelWorks Foundation.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

New treatments are coming for liver-damaging virus.

Alex Monto, UC San Francisco

Hepatitis C virus — not AIDS-causing HIV — is the leading chronic virus infection leading to death in the United States, and its victims most often are baby boomers. More than half who are infected do not know it.

Researchers from the U.S. Centers for Disease Control and Prevention (CDC) found in a study published in the Feb. 21 issue of the Annals of Internal Medicine that hepatitis C had overtaken HIV as a cause of death in the United States by 2007.

Deaths in the United States due to HIV infection have been steadily decreasing, and  dropped below 13,000 in 2007, while deaths from hepatitis C infection have been steadily increasing, first surpassing 15,000 per year in 2007.

The good news, according to UC San Francisco liver specialist Alex Monto, M.D., is that there has been progress in fighting both diseases, and the kinds of drug combination strategies that have done so much to transform HIV infection from a death sentence to a manageable disease are poised to further boost cure rates for those infected with hepatitis C.

“We know that not enough people with risk factors get tested,” Monto says. “There are a lot of people walking around with hepatitis C who don’t know it.”

Monto directs the liver clinic at the UCSF-affiliated San Francisco Veteran’s Affairs Medical Center, one of four hepatitis C centers nationally within the VA system. Like boomers, veterans are disproportionately affected by hepatitis C. The VA cares for 165,000 patients who are chronically infected with the virus.

Hepatitis C infects 3 million in the U.S.

Chronic Hepatitis C has been diagnosed in about three million people in the United States. It often causes no symptoms, and many who have been infected for years or even decades may remain unaware of it until symptoms finally appear. The ultimate cause of death attributable to chronic infection is cirrhosis or liver cancer, although the disease progresses to cirrhosis in fewer than half of cases. There is no vaccine.

“The main risk factor in the United States is past injection-drug use,” Monto says. “The others most at risk are those who received blood transfusions before 1992,” Monto says, referring to the year when high-quality screening of the blood supply was implemented.

[Related: Hear Alex Monto talk about hepatitis C]

Compared to HIV or hepatitis B, the risk of hepatitis C being transmitted by sex is low, Monto says, but among men who have sex with men there has been an increase in reports of the virus being sexually transmitted, more so among those who are infected with HIV.

“Anybody with a history of ever being exposed to injection drugs or who received a transfusion before the blood supply was screened should be tested,” Monto says. “That’s not controversial at all. What has been controversial is whether or not all baby boomers should be screened.”

Another study in this week’s edition of the journal suggests that a one-time blood test ordered by primary care providers to screen for antibodies to hepatitis C in those born between 1945 and 1965 would be cost effective — costing $2,874 for each chronically infected patient identified — and would lead to the identification of more than 800,000 previously undiagnosed cases.

Those who are chronically infected may be able to reduce the likelihood of disease progression by avoiding alcohol, by maintaining a healthy weight, and by being vaccinated against hepatitis A and hepatitis B, Monto says.

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Clinical trials aim to tackle lethal form of prostate cancer.

Davide Ruggero, UC San Francisco

Uncovering the network of genes regulated by a crucial molecule involved in cancer called mTOR, which controls protein production inside cells, researchers at the University of California, San Francisco, have discovered how a protein “master regulator” goes awry, leading to metastasis, the fatal step of cancer.

Their work also pinpoints why past drugs that target mTOR have failed in clinical trials, and suggests that a new class of drugs now in trials may be more effective for the lethal form of prostate cancer for which presently there is no cure.

Described this week in the journal Nature, the protein mTOR is a “master regulator” of human protein synthesis. It helps normal cells sense nutrients and control cell growth and metabolism. But in many forms of cancer, this process goes awry, and mTOR reprograms normal cells to aberrantly divide, invade and metastasize.

“Many human cancers show hyperactivation of this pathway,” said Davide Ruggero, Ph.D., an associate professor of urology and member of the Helen Diller Family Comprehensive Cancer Center and the Multiple Myeloma Translational Initiative at UCSF. “Until now, we have not known how hyperactive mTOR perturbs the synthesis of certain proteins leading to fatal cancer.”

In the human body, mTOR is a molecular sensor that helps cells respond to favorable or unfavorable environments. Under ordinary conditions, it acts as a master regulator of genes that induce cells to growth and divide. In times of scarcity, when somebody is starving for instance, mTOR shuts down much of the machinery that makes proteins so that an organism can conserve energy.

In cancer, this careful balance is lost. The rogue mTOR protein goes haywire and signals tumor cells to become bigger to divide, undergo metastasis and invade new, healthy tissues. Metastasis is the primary cause of cancer patient death.

“We are now discovering that during tumor formation mTOR leads to metastasis by altering the synthesis of a specific group of proteins that make the cancer cells move and invade normal organs,” Ruggero said.

In their research, Ruggero and his colleagues identified the players that instruct or execute decisions made by mTOR, and they discovered how mTOR deregulates one of the very last stages of gene expression — just before they are translated into proteins by large molecular machines known as ribosomes.

They used a method called ribosome profiling pioneered by UCSF professor Jonathan S. Weissman and Nicholas T. Ingolia at the Carnegie Institution for Science, also authors on the paper. This method basically allows researchers to collect the millions of ribosomes from inside cells and determine which genes they are turning into proteins.

Experiments focus on prostate cancer

Because it plays such a crucial role in cancer biology, mTOR is also an active target for drug development. Several compounds that block this protein, including the drug Rapamycin, have already gone through clinical trials as single agents for treating various forms of cancer such as prostate cancer — without great success.

The new research suggests why drugs like Rapamycin have failed. The problem, said Ruggero, is that they block mTOR, but not completely. The newer drugs, however, block mTOR more completely.

The difference is akin to holding a door shut with a piece of tape versus locking it and breaking the key off in the lock so no one can re-open it.

When drugs like Rapamycin fail to completely stop mTOR from working, they allow it to continue pushing a cancer cell toward malignancy. Some newer compounds that block mTOR do so more completely, and the team led by Ruggero showed in preclinical experiments that this effectively hobbles the cancer cells.

Specifically they tested an experimental drug called INK128, derived from a compound discovered in the UCSF laboratory of Kevan Shokat, Howard Hughes Medical Investigator, professor and chair of cellular and molecular pharmacology and another author on the paper. This compound is now in clinical trials for different types of cancers and is being developed by a team led by Christian Rommel in the La Jolla company Intellikine Inc., the home of some of the co-authors in the Nature manuscript.

In their research, Ruggero and his colleagues showed that a mouse model of human prostate cancer treated with INK128 did not metastasize. They also showed that the new drug has a strong therapeutic effect on human prostate cancer cells.

“While the experiments were primarily focused in prostate cancer, we believe this work is widely applicable in many tumor types because mTOR is a critical regulator of so many cancers,” said first author Andrew Hsieh, M.D., a clinical oncologist in the UCSF Department of Medicine, Division of Hematology/Oncology and a senior member of the Ruggero laboratory. “For example, clinicians Jeff Wolf and Tom Martin are now testing INK128 here at UCSF, in multiple myeloma patients,” Ruggero said.

The research also found that INK128 works better by also restraining abnormal protein synthesis when mTOR is hyperactive. ”Deregulations in protein synthesis is now becoming a hallmark of cancer, and we are very excited by the opportunity to target the aberrant protein synthesis apparatus in many cancers,” Ruggero said.

Andrew C. Hsieh, Yi Liu, Merritt P. Edlind, Nicholas T. Ingolia, Matthew R. Janes, Annie Sher, Evan Y. Shi, Craig R. Stumpf, Carly Christensen, Michael J. Bonham, Shunyou Wang, Pingda Ren, Michael Martin, Katti Jessen, Morris E. Feldman, Jonathan S. Weissman, Kevan M. Shokat, Christian Rommel and Davide Ruggero are being published by the journal Nature as an Advance Online Publication.

This work was funded by the National Institutes of Health, the Cancer Research Coordinating Committee, the American Cancer Society and the Phi Beta Psi sorority. Additional support was provided through Prostate Cancer Foundation and a Department of Defense Prostate Cancer Training Award. Ruggero is a Leukemia & Lymphoma Society Scholar.

Some of the authors of the paper are employed by Intellikine Inc. One author (Kevan Shokat) is a stockholder and consultant for Intellikine.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Berkeley Lab researchers find new evidence on how cholesterol gets moved from HDLs to LDLs.

Optimized negative-staining EM of CETP shows the protein’s banana shape

Researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) have found new evidence to explain how cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol from “good” high density lipoproteins (HDLs) to “bad” low density lipoproteins (LDLs). These findings point the way to the design of safer, more effective next generation CETP inhibitors that could help prevent the development of heart disease.

Gang Ren, a materials physicist and electron microscopy expert with Berkeley Lab’s Molecular Foundry, a DOE nanoscience research center, led a study in which the first structural images of CETP interacting with HDLs and LDLs were recorded. The images and structural analyses support the hypothesis that cholesterol is transferred from HDLs to LDLs via a tunnel running through the center of the CETP molecule.

“Our images show that CETP is a small (53 kilodaltons) banana-shaped asymmetric molecule with a tapered N-terminal domain and a globular C-terminal domain,” Ren says. “We discovered that the CETP’s N-terminal penetrates HDL and its C-terminal interacts with LDL forming a ternary complex. Structure analyses lead us to hypothesize that the interaction may generate molecular forces that twist the terminals, creating pores at both ends of the CETP. These pores connect with central cavities in the CETP to form a tunnel that serves as a conduit for the movement of cholesterol from the HDL.”

Ren reports the results of this study in a paper in the journal Nature Chemical Biology titled “Structure basis of transfer between lipoproteins by cholesteryl ester transfer protein.” Co-authoring this paper were Lei Zhang, Feng Yan, Shengli Zhang, Dongsheng Lei, M. Arthur Charles, Giorgio Cavigiolio, Michael Oda, Ronald Krauss, Karl Weisgraber, Kerry-Anne Rye, Henry Powna and Xiayang Qiu.

Cardiovascular or heart disease, mainly atherosclerosis, remains the leading cause of death in the United States and throughout the world. Elevated levels of LDL cholesterol and/or reduced levels of HDL cholesterol in human plasma are major risk factors for heart disease. Since CETP activity can reduce HDL-cholesterol concentrations and CETP deficiency is associated with elevated HDL-cholesterol levels, CETP inhibitors have become a highly sought-after pharmacological target for the treatment of heart disease. However, despite this intense clinical interest in CETP, little is known concerning the molecular mechanisms of CETP-mediated cholesterol transfers among lipoproteins, or even how CETP interacts with and binds to lipoproteins.

“It has been very difficult to investigate CETP mechanisms using conventional structural imaging methods because interaction with CETP can alter the size, shape and composition of lipoproteins, especially HDL,” Ren says. “We were successful because we used our optimized negative-staining electron microscopy protocol that allows us to flash-fix the structure and efficiently screen more than 300 samples prepared under different conditions.”

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Study seeks to ID treatment paramedics can administer to cardiac arrest victims in the field.

Sudden cardiac arrest (SCA) is the leading cause of death in the United States. This form of heart attack kills 325,000 people every year, representing one death every two minutes. Almost all SCA victims die before they even reach a hospital. To identify a drug that paramedics can use in the field, UC San Diego Health System has opened a clinical trial to evaluate two medications to help restore the heart beat.

“Only five percent of sudden cardiac arrest victims survive their heart attack,” said Daniel Davis, M.D., UC San Diego director of resuscitation science in the Department of Emergency Medicine. “For more than 30 years we’ve been looking for an anti-arrhythmic drug to treat ventricular tachycardia, or what we call shockable rhythm, but we have not found a drug that consistently improves patient outcomes. This clinical trial will help us determine if either the drugs amiodarone or lidocaine may help prevent death.”

This NIH-funded clinical trial consists of three study arms to compare lidocaine, amiodarone and a placebo. The primary objective is to determine if survival is improved with a new formulation of amiodarone and to determine if amiodarone or lidocaine is more effective. The drugs are delivered by injection.

“If there is clear evidence that lidocaine or amiodarone works better in saving lives, we hope to end the study early to incorporate the drug into everyday treatment practice,” said Davis. “This effort could help save dozens of lives each year in San Diego and hundreds across California.”

Currently in San Diego there is no anti-arrhythmic being used by paramedics to treat patients. Either cardiopulmonary resuscitation or the use of a defibrillator to shock the heart into normal rhythm, are the only two treatment options.

This clinical trial will be conducted under “Exemption from Informed Consent” guidelines, which have been approved by the U.S. Department of Health and Human Services and the Food and Drug Administration. This means that the drug will be administered by paramedics to patients whose hearts have stopped beating. If a family member is present, they will be informed of the study and given the option of refusing participation.

“A patient in cardiac arrest is not capable of communication. Nor is it realistic to identify and contact family members in a timely fashion who can consent on their behalf,” said Davis. “When a patient is in critical need of rapid medical treatment, the priority is to provide treatment. Every second counts to save the heart and brain.”

The trial will launch this spring. More than 3,000 patients will be enrolled over the course of three to four years in ten different sites across North America.

This clinical trial is part of The Resuscitation Outcomes Consortium (ROC) which was created to conduct clinical research in the areas of cardiopulmonary resuscitation and traumatic injury. ROC consists of 10 Regional Clinical Centers and a Data and Coordinating Center that will provide the necessary infrastructure to conduct multiple collaborative trials to aid rapid translation of promising scientific and clinical advances to improve resuscitation outcomes. Trials may evaluate existing or new therapies as well as clinical management strategies such as novel hemorrhage control strategies and alternative methods of delivering CPR or defibrillation.

Researchers call for increased screening for patients taking the the medication.

Tenofovir, one of the most effective and commonly prescribed antiretroviral medications for HIV/AIDS, is associated with a significant risk of kidney damage and chronic kidney disease that increases over time, according to a study of more than 10,000 patients led by researchers at the San Francisco VA Medical Center and the University of California, San Francisco.

The researchers call for increased screening for kidney damage in patients taking the drug, especially those with other risk factors for kidney disease.

In their analysis of comprehensive VA electronic health records, the study authors found that for each year of exposure to tenofovir, risk of protein in urine — a marker of kidney damage — rose 34 percent, risk of rapid decline in kidney function rose 11 percent and risk of developing chronic kidney disease (CKD) rose 33 percent. The risks remained after the researchers controlled for other kidney disease risk factors such as age, race, diabetes, hypertension, smoking and HIV-related factors.

For individual patients, the differences in risk between users and non-users of tenofovir for each year of use were 13 percent vs. 8 percent for protein in urine, 9 percent vs. 5 percent for rapidly declining kidney function and 2 percent vs. 1 percent for CKD. “However, these numbers are based on the average risks in our study population, and patients with more risk factors for kidney disease would be put at proportionately higher risk,” said principal investigator Michael G. Shlipak, M.D., M.P.H., chief of general internal medicine at SFVAMC and professor of medicine and epidemiology and biostatistics at UCSF.

[Related: Tenofovir: Q&A for patients and providers]

Patients were tracked for an average of 1.2 years after they stopped taking tenofovir. They remained at elevated risk for at least six months to one year compared with those who never took the drug, suggesting that the damage is not quickly reversible, said Shlipak. “We do not know the long-term prognosis for these patients who stop tenofovir after developing kidney disease,” he cautioned.

The implications for patients already on or starting antiretroviral therapy are “mixed,” said Shlipak. “The best strategy right now is to work with your health care provider to continually monitor for kidney damage. Early detection is the best way to determine when the risks of tenofovir begin to outweigh the benefits.”

Shlipak noted that HIV, itself, increases the risk of kidney damage, while modern antiretroviral treatments clearly reduce that overall risk. “Patients need to be aware of their kidney disease risks before they start therapy, and this should influence the medications that they choose in consultation with their doctor,” he said. “For an otherwise healthy patient, the benefits of tenofovir are likely to exceed the risks, but for a patient with a combination of risk factors for kidney disease, tenofovir may not be the right medication.”

Tenofovir is used to decrease viral load and increase immune cell count in people infected with the virus. It is currently considered the preferred first line treatment for HIV because of its potency, overall low toxicity, and convenience of dosing. It is sold under a variety of names, by itself and in combination with other medications.

The study examined the medical records of 10,841 HIV-positive veterans in the national VA health care system who were new users of antiretroviral therapy from 1997 to 2007. It was published electronically in the journal AIDS on Jan. 9.

Lead author Rebecca Scherzer, Ph.D., a researcher and statistician at SFVAMC and UCSF, said that the observational study was the largest and most conclusive indication so far of tenofovir’s association with kidney damage. “There have been a number of previous, smaller studies suggesting that this drug might be associated with kidney disease, but the results were mixed,” she said. “Those studies may have missed this association because they were too small, lacked appropriate lab data or excluded subjects with pre-existing renal impairment or risk factors for kidney disease.”

To be sure that tenofovir was the culprit, Scherzer and her colleagues looked for associations between 18 other antiretroviral medications and the same three measures of kidney disease:  protein in urine, rapid decline in function and progression to CKD. None were associated with higher risk.

Shlipak noted that the study results are particularly strong because two of the risk factors — decline in function and CKD — indicate kidney function, while protein in urine indicates physical damage to the kidney. “These are independent markers,” he said. “To see the same drug cause both types of kidney disease gives you a very objective signal that something real is happening here.”

Shlipak emphasized that, despite tenofovir’s association with progressive kidney disease, it is an important component of effective antiretroviral therapy that may be required in many patients to control viral load.

The VA is the largest provider of HIV care in the United States, said Shlipak. “We could not have done this work without access to the VA’s system of electronic medical records,” he said. “In particular, the data kept by the VA Clinical Care Registry, located at the VA Palo Alto Health Care System, were essential to this study.”

Co-authors of the study are Michelle Estrella, M.D., of Johns Hopkins School of Medicine; the late Andy I. Choi, M.D., M.A.S., of SFVAMC and UCSF; Steven G. Deeks, M.D., of San Francisco General Hospital; and Carl Grunfeld, M.D., Ph.D., of SFVAMC and UCSF.

The study was supported by funds from the National Institutes of Health, the National Center for Research Resources, the American Heart Association and the Department of Veterans Affairs, some of which were administered by the Northern California Institute for Research and Education.

NCIRE — The Veterans Health Research Institute — is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.

SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

UC Riverside scientists identify a protein that plays a crucial role in learning and memory.

Iryna Ethyll (left) and Crystal Pontrello, UC Riverside

Biomedical scientists at the University of California, Riverside, have identified a new link between a protein called beta-arrestin and short-term memory that could open new doors for the therapeutic treatment of neurological disorders, particularly Alzheimer’s disease.

Beta-arrestin is expressed in various cells of the body, including cells of the hippocampus, the region of the brain that is involved in learning and the formation of short-term memories. Beta-arrestin, the absence of which impairs normal learning in mice, is one of many “scaffolding proteins” — proteins that support the connections between neurons in the brain.

As our brain develops, new connections called synapses are formed between neurons. In the hippocampus, the formation of synapses is a continuous process. As we learn something new, new connections are formed and some old ones become stronger through a process known as long-term potentiation (LTP). But because brains have only a limited capacity, other old connections must disassemble through a process known as long-term depression (LTD) in order for new synapses to form.

The researchers report online last week in the Proceedings of the National Academy of Sciences that beta-arrestin plays an important role in the plasticity of synaptic connections and LTD by regulating the “actin cytoskeleton,” a dynamic filamentous network of proteins that forms the “backbone” of neurons and is involved in forming new and disassembling old synaptic connections.

“In some pathological conditions such as Alzheimer’s disease, loss of the old synaptic connections far exceeds the formation of new ones, resulting in overall loss of synapses and short-term memory loss,” said Iryna M. Ethell, an associate professor of biomedical sciences and the lead author of the research paper. “Our work, done on mice, shows that if beta-arrestin is removed from neurons, this loss of synapses is prevented.  But we also know that beta-arrestin is required for normal learning and memory; so a fine balance needs to be established. This balance could be easily achieved by pharmaceutical drugs in the future.”

This is the first time researchers anywhere have linked beta-arrestin to Alzheimer’s and learning/memory.

Ethell explained that beta-arrestin can be visualized as energy supplied to a puppeteer (actin cytoskeleton) controlling the strings of the puppets (inter-neuronal connections).  For normal learning to take place, the puppeteer needs to move the strings in a specific order.  But in patients with Alzheimer’s, this supply of energy over-activates and the strings are pulled in a disorderly fashion that results in the strings being broken (loss of synapses) and the puppets collapsing. While the removal of beta-arrestin would prevent this collapse, a complete loss of beta-arrestin would mean no movement of the puppets at all (that is, no learning in the brain), which is equally undesirable.

“A selective tuning of beta-arrestin activity is therefore necessary to partially reduce synapse disassembly,” said Crystal G. Pontrello, the first author of the research paper and a postdoctoral researcher in Ethell’s lab.  “What you want, ideally, is the elimination of only some unused old synaptic connections so that there is room to make new connections.”

Ethell and Pontrello were joined in the research by UC Riverside’s Min-Yu Sun, Alice Lin, Todd A. Fiacco and Kathryn A. DeFea.

The research was supported by a grant to Ethell by the National Institutes of Health.