Source: http://pe.com/localnews/inland/stories/…

By DAVID DANELSKI
The Press-Enterprise

Dr. Julia Ljubimova found something disturbing when she probed the brains of rats exposed to air pollution: The dirty air appeared to trigger changes indicating the earliest stage of brain tumors.

Ljubimova, an oncologist and researcher at Cedars-Sinai Medical Center in Los Angeles, stressed that she is not ready to say air pollution is a cause of brain cancer.

“I don’t want to scare anyone, because this is preliminary data,” she said. “But we found something very important.”

Her work suggests that fine particles like those found in diesel soot can switch on the tumor genes that many people inherit, jump-starting the disease process that results in brain tumors.

Hundreds of studies have linked air pollution to early deaths, heart attacks, reduced lung function, lung cancer and various other health problems. Ljubimova is among a handful of scientists who are focused on finding out what air pollution does to people’s brains.

The first results from the fledging research field are creating concern.

In addition to Ljubimova’s work:

A University of Southern California epidemiologist reported to air pollution regulators last year that children living in Southern California’s more polluted areas — including the Inland area — had a higher risk of developing brain tumors.

A UC Irvine toxicologist reported last month at a Society of Toxicology meeting in Seattle that mice exposed to air pollution near the Coliseum sports stadium in central Los Angeles had brain inflammation and cell injuries associated with the first stages of diseases like Alzheimer’s and Parkinson’s.

Last year, Danish researchers monitored brain waves of people exposed to diesel exhaust and found that the pollution increased brain-wave activity, suggesting pollution may alter brain function. Their research was published last month in the journal Particle and Fibre Toxicology.

The findings so far don’t prove that air pollution causes brain disease, “but it is intriguing and worrisome,” Roberta McKean-Cowdin said. She is the USC epidemiologist who analyzed health data to find an apparent correlation between pollution and brain tumors in children from newborns to 5 years of age.

Dr. Keith Black, who is chairman of the Cedars-Sinai neurosurgery department and oversees Ljubimova’s project, hopes the work will lead to discoveries that will allow doctors to prevent or treat the disease. The research also could identify specific particles in diesel exhaust or other pollution that cause cancer, allowing development of engines that don’t emit those particles.

Brain cancer, which can destroy the mind and body simultaneously, killed an estimated 12,700 people in the United States last year.

Black, who has performed more than 7,000 brain cancer surgeries, had seen first-hand the devastation the disease inflicts on victims and their loved ones. It motivated him to pursue research.

“It is a lot easier to prevent the formation of cancer than it is to treat cancer,” he said.

Research Takes Root

The idea for air pollution research at Cedars-Sinai came out of a 2002 Christmas party conversation between Black and William Burke, a 14-year member of the governing board of the South Coast Air Quality Management District, which regulates polluters in Orange County and most populated areas of San Bernardino, Riverside and Los Angeles counties.

They talked about the rise in brain cancer cases among children and how, as studies had shown, firefighters exposed to diesel exhaust in their fire stations were more likely to develop brain cancer than people in other occupations, Black recalled.

At the time, research had shown that the microscopic particles of pollution could work their way through blood vessel walls and enter the brain, an organ normally protected from such invasions.

Burke took the conversation seriously.

“That was something we needed to we know more about right away,” he said.

In 2003, Burke persuaded his colleagues to form the Brain and Lung Tumor and Air Pollution Foundation to fund research. Using money the South Coast district collects through fines on polluters, the foundation so far has provided about $2.1 million to molecular biology work at Cedars-Sinai and $178,000 to USC to examine brain cancer incidence among people living polluted areas, including the Inland region.

Burke said he plans to ask the board this year to dedicate 5 to 10 percent of future fine revenues to such research. The amounts vary, but the air district expects to collect about $4.1 million in fines this fiscal year.

Genes and Pollution

Ljubimova, a native of Azerbaijan and daughter of a Soviet military doctor, studied medicine in Kiev, Ukraine. She treated cancer patients in Moscow, then took a research position at Baylor College of Medicine in Houston in 1990. She joined Cedars-Sinai three years later and is now molecular oncology director for the hospital’s Department of Neurosurgery.

She has probed the biochemistry of breast and liver cancer in a quest for better treatments and cures. She now focuses on the genetic mechanisms involved in brain and breast tumors.

Thousands of genes within the DNA of a cell carry the instructions to build every component of an organism’s life. A gene contains blueprints to build the proteins, for example, that allow a red blood cell to carry oxygen and distribute it through the body. Other genes determine eye and hair color, height and whether a person will tend to be fat or thin.

Some genes contain instructions to grow cells that compose deadly tumors. If such genes become active, cancer forms.

To test how fine particles affect the brain, Ljubimova divided about 180 laboratory rats into groups and exposed them to three sizes of pollution particles for periods ranging from two weeks to 10 months. The rats were subjected to air many times more polluted than the air Southern Californians breathe.

After each exposure period, the rats were euthanized and their brain tissue examined for gene activity.

In the pollution-exposed rats, the genes associated with brain tumors were more active than in the rats that breathed purified air. The same genes are found in human tumor samples collected by the medical center.

The Cedars-Sinai research also found that the longer the rats breathed polluted air, the more active the cancer genes.

The pollution “might trigger or turn on the process or processes for several pathways that transform normal cells into malignant cells,” Ljubimova said.

Her findings will be presented at an international conference in June. The medical center plans to seek grants to continue her investigation, with longer pollution exposures and further analysis to learn why tumor genes are activated.

“We have to do more molecular biology to learn the mechanism,” she said.

Message in the Numbers

Instead of studying rats, USC’s McKean-Cowdin is looking for clues in illnesses that already have happened. She examined records from 496 brain cancer cases among Southern California infants and children between 1991 and 2002.

Her preliminary finding: People living in areas with higher levels of fine-particle pollution have a higher risk for brain cancer. That holds true in the Inland region, she said.

Northwest Riverside County and southwest San Bernardino County regularly exceed federal and state health standards for fine-particle pollution.

McKean-Cowdin said her research is undergoing further analysis and is expected to be published this year in a scientific journal. Her next step, if she can find funding, will to be examine potential links between air pollution and children as old as 19.

Cancer is caused by numerous factors, including genetics and exposure to toxic substances in the environment. Black said.

“It may be air pollution is one of those components,” he said.

Reach David Danelski at 951-368-9471 or

Source: http://usc.edu/uscnews/stories/15032.html

Fasting for two days protects healthy cells against chemotherapy, according to a study appearing online the week of Mar. 31 in PNAS Early Edition.

Mice given a high dose of chemotherapy after fasting continued to thrive. The same dose killed half the normally fed mice and caused lasting weight and energy loss in the survivors.

The chemotherapy worked as intended on cancer, extending the lifespan of mice injected with aggressive human tumors, reported a group led by Valter Longo of the University of Southern California.

Test tube experiments with human cells confirmed the differential resistance of normal and cancer cells to chemotherapy after a short period of starvation.

Making chemotherapy more selective has been a top cancer research goal for decades. Oncologists could control cancers much better, and even cure some, if chemotherapy were not so toxic to the rest of the body.

Experts described the study as one of a kind.

“This is a very important paper. It defines a novel concept in cancer biology,” said cancer researcher Pinchas Cohen, professor and chief of pediatric endocrinology at the University of California, Los Angeles.

“In theory, it opens up new treatment approaches that will allow higher doses of chemotherapy. It’s a direction that’s worth pursuing in clinical trials in humans.”

Felipe Sierra, director of the Biology of Aging Program at the National Institute on Aging, said: “This is not just one more anti-cancer treatment that attacks the cancer cells. To me, that’s an important conceptual difference.”

Sierra was referring to decades of efforts by thousands of researchers working on “targeted delivery” of drugs to cancer cells. Study leader Longo focused instead on protecting all the other cells.

Sierra added that progress in cancer care has made patients more resilient and able to tolerate fasting, should clinical trials confirm its usefulness.

“We have passed the stage where patients arrive at the clinic in an emaciated state. Not eating for two days is not the end of the world,” Sierra said.

“This could have applicability in maybe a majority of patients,” said David Quinn, a practicing oncologist and medical director of USC Norris Hospital and Clinics. He predicted that many oncology groups would be eager to test the Longo group’s findings, and advised patients to look for a clinical trial near home.

Longo, an anti-aging researcher who holds joint appointments in gerontology and biological sciences at USC, said that the idea of protecting healthy cells from chemotherapy may have seemed impractical to cancer researchers, because the body has many different cells that respond differently to many drugs.

“It was almost like an idea that was not even worth pursuing. In fact it had to come from the anti-aging field, because that’s what we focus on: protecting all cells at once,” Longo said.

“What really was missing was a perspective of someone from the aging field to give this field a boost,” UCLA’s Cohen said.

The idea for the study came from the Longo group’s previous research on aging in cellular systems, primarily lowly baker’s yeast.

About five years ago, Longo was thinking about the genetic pathways involved both in the starvation response and in mammalian tumors.

When the pathways are silenced, starved cells go into what Longo calls a maintenance mode characterized by extreme resistance to stresses. In essence the cells are waiting out the lean period, much like hibernating animals.

But tumors by definition disobey orders to stop growing because the same genetic pathways are stuck in an “on” mode.

That could mean, Longo realized, that the starvation response might differentiate normal and cancer cells by their stress resistance, and that healthy cells might withstand much more chemotherapy than cancer cells.

The shield for healthy cells does not need to be perfect, Longo said. What matters is the difference in stress resistance between healthy and cancerous cells.

During the study, conducted both at USC and in the laboratory of Lizzia Raffaghello at Gaslini Children’s Hospital in Genoa, Italy, the researchers found that current chemotherapy drugs kill as many healthy mammalian cells as cancer cells.

“(But) we reached a two to five-fold difference between normal and cancer cells, including human cells in culture. More importantly, we consistently showed that mice were highly protected while cancer cells remained sensitive,” Longo said.

If healthy human cells were just twice as resistant as cancer cells, oncologists could increase the dose or frequency of chemotherapy.

“We were able to reach a 1,000-fold differential resistance using a tumor model in baker’s yeast. If we get to just a 10-20 fold differential toxicity with human metastatic cancers, all of a sudden it’s a completely different game against cancer,” Longo said.

“Now we need to spend a lot of time talking to clinical oncologists to decide how to best proceed in the human studies.”

Edith Gralla, a research professor of chemistry at UCLA, said: “It is the sort of opposite of the magic bullet. It’s the magic shield.”

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Funding from the study came from NIA (part of the National Institutes on Health), the USC Norris Cancer Center and the Associazione Italiana per la Lotta al Neuroblastoma.

USC graduate student Changhan Lee and Gaslini’s Raffaghello performed key experiments. The other authors were Fernando Safdie, Min Wei and Federica Madia of USC, and Giovanna Bianchi of Gaslini.

Longo has been studying aging at the cellular level for 15 years, and has published in the nation’s leading scientific journals. He is the Albert L. and Madelyne G. Hanson Family Trust Associate Professor in the USC Leonard Davis School of Gerontology with joint appointments as associate professor of biological sciences in the USC College of Letters, Arts and Sciences, and in the Norris Cancer Center.

FOR CLINICIANS AND PATIENTS

Fasting before chemotherapy has unknown risks and benefits for humans, Longo cautioned. Only clinical trials can establish the effectiveness and safety of fasting before chemotherapy.

“Don’t try and do this at home. We need to do the studies,” said Quinn, the USC Norris oncologist.