U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
Eunice Kennedy Shriver National Institute of Child Health and Human

Embargoed for Release: Tuesday, February 1, 2011

Metastasis

NIH researchers seek to develop test to guide treatment

Researchers at the National Institutes of Health and the University of Hong Kong have discovered that high levels of a particular protein in cancer cells are a reliable indicator that a cancer will spread.

By measuring the protein’s genetic material in tumors that had been surgically removed from patients, along with measuring the genetic material from surrounding tissue, the researchers could predict at least 90 percent of the time whether a cancer would spread within two years.

The findings raise the long term possibilities of new tests to gauge the likelihood that a cancer will spread and, ultimately, of a treatment that could prevent cancer from spreading.

The protein, known as CPE-delta N, is a form of carboxypeptidase E (CPE).  Ordinarily, CPE is involved in processing insulin and other hormones.  CPE-delta N, a variant of CPE, was present in high amounts in tumors that had spread and, to a much lesser degree, in surrounding tissues.

Cancer cells can break away from a primary tumor and spread, or metastasize, to other parts of the body, where they form new tumors.  Metastatic cancer is often fatal, and health care practitioners seek to contain cancer early, before it can metastasize.

“Testing for CPE-delta N, if combined with existing diagnostic methods, offers the possibility of more accurately estimating the chances that a cancer will spread,” said Alan E. Guttmacher, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which supported the study.  “Conceivably, a patient’s CPE-delta N levels could be a key guide in individualizing their cancer care to improve outcome.”

The researchers estimated the likelihood of metastasis in tumor samples and tissues from patients with liver cancer (http://www.cancer.gov/cancertopics/types/liver/) and two rare tumors, pheochromocytoma and paraganglioma (http://www.cancer.gov/cancertopics/types/pheochromocytoma/).  They found that tumor samples from patients whose cancers had later metastasized had elevated levels of CPE-delta N.

Tests indicating high levels of the protein predicted the spread of a cancerous tumor even when conventional staging-diagnostic techniques to gauge the extent and seriousness of a cancer-indicated that spread was unlikely.  The finding raises the possibility that testing for CPE-delta N might be used in combination with conventional staging to further refine treatment.  For example, if conventional staging indicated that a cancer was unlikely to spread, but a patient’s tumor had high CPE-delta N levels, that patient might be referred for more intensive therapies normally reserved for higher stage cancers.

The study’s senior authors were Y. Peng Loh of NICHD’s Section on Cellular Neurobiology and Ronnie Poon from the University of Hong Kong.  Other authors were from the NICHD, University of Hong Kong, the Lawson Health Research Institute in Ontario, Canada; the NIH’s National Cancer Institute (NCI); and the Warren Grant Magnuson Clinical Center at NIH.  The research was supported in part by NICHD, NCI, The University of Hong Kong and by the Canadian government.

The findings appear in the Journal of Clinical Investigation.

The researchers tested for CPE-delta N indirectly, by measuring levels of a molecule that assists in manufacturing the protein.  RNA (ribonucleic acid) works with the information in a gene to make a particular protein-in this case, CPE-delta N.

In an analysis of tissue from 99 patients with liver cancer, the researchers compared the amount of CPE-delta N RNA from the patients’ tumors with the RNA levels in surrounding tissue.

The researchers found that when the level of CPE delta-N RNA in tumors was more than twice that in the surrounding tissue, the cancer was highly likely to return or to metastasize within two years.  At or below this threshold level, the cancer was much less likely to recur.  Using this threshold measure, the researchers accurately predicted metastasis or recurrence in more than 90 percent of cases.  Conversely, their predictions that tumors would not return in the two-year period were accurate 76 percent of the time.

Next, the researchers measured CPE-delta N RNA levels from stored tumor tissue originally removed from 14 patients with pheochromocytoma, a rare tumor of the adrenal glands, and paraganglioma, a rare tumor primarily occurring in the adrenals but sometimes in other parts of the body.  Because the adrenal glands are very small, tissue surrounding the tumor was not obtainable, so the researchers measured the amount of CPE-delta N RNA in the tumor tissue only.  The number of copies ranged from 150,000 to 15 million per 200 micrograms of tissue.

In all of the cases where cancer was found to have recurred or metastasized, CPE-delta N RNA levels were greater than 1 million.  The researchers found no metastasis or recurrence in cases in which tumors had less than 250,000 copies.  Patients’ status was tracked for up to eight years.

In addition, the researchers examined cells from liver, breast, colon, and head and neck, tumors and found that those known to spread most aggressively had the highest levels of CPE-delta N RNA.

The researchers next tested a potential strategy for preventing the spread of cancer by halting the production of CPE-delta N in two different mouse models.  The strategy involved treating metastatic tumors with antisense RNA, which binds to RNA, preventing it from making a protein.

In the first experimental model, the researchers transplanted highly metastatic liver cancer cells beneath the skin of mice.  Half the transplants were first treated with antisense RNA specific for CPE-delta N, the other half were not.  After 30 days, the tumors in the mice not treated with antisense RNA for CPE-delta N were much larger than the treated tumors in the remaining mice.  Next, the researchers removed the tumors from the first set of mice and transplanted them into the livers of a second group of mice.  After 35 days, only the untreated tumors had spread and formed new tumors.

Dr. Loh explained that the method used in the study might some day be used to treat cancers in human beings.  Currently, there are no means to deliver the antisense RNA to tumor cells.  A potential approach might involve modifying a virus to carry the antisense RNA into cells.

Similarly, further research might lead to the development of drugs or other measures to block CPE-delta N and so prevent cancer from spreading.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.  For more information, visit the Institute’s Web site at <http://www.nichd.nih.gov/>.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and

Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <www.nih.gov>.


GoogleNews.com, FORBES.com, February 1, 2011, by Maria Cheng, LONDON — Scientists have identified five new genes linked to Parkinson’s disease in a large genetic analysis of the illness, according to a new study.

After reviewing nearly 8 million possible genetic mutations, researchers pinpointed five genes connected to Parkinson’s disease. Previously, six other genes were identified, and experts say there is now increasing proof the degenerative disease is sparked by peoples’ genes.

The discovery doesn’t mean there are any new treatments just yet, but experts are optimistic they are getting closer.

“The major common genetic variants for Parkinson’s have been found,” said Nick Wood, a professor at the Institute of Neurology at University College London, one of the researchers who led the study. “We haven’t put together all the pieces of the puzzle yet, but we’re not that far off,” he said. He predicted a diagnostic test might be ready within a few years.

Until recently, scientists hadn’t been sure what caused Parkinson’s disease, but assumed environmental factors such as exposure to chemicals or past head injuries were largely to blame.

Scientists analyzed genetic samples from more than 12,000 people with Parkinson’s disease and more than 21,000 from the general population in Europe and the U.S. They found people with the highest number of mutations in the 11 genes linked to Parkinson’s were two-and-a-half times more likely to develop the disease than people who had the least amount of mutations.

The average person has a 2.5 percent chance of developing Parkinson’s disease in their lifetime, and the risk for people whose close relatives have the illness is about six percent.

The research was paid for by the Wellcome Trust, the National Institute of Aging and the U.S. Department of Defense. It was published online Wednesday in the medical journal Lancet.

Parkinson’s is a degenerative brain disease that strikes when brain cells don’t make enough of the chemical dopamine. That leads to symptoms including tremors, rigidity and slowness of movement. There are limited treatments and no cure for the disease. It mostly affects people over 50, though younger people, including actor Michael J. Fox, sometimes develop the disease.

Experts said Parkinson’s disease was likely the result of a complex interaction between genetics and environmental risk factors.

In an accompanying commentary, scientists said identifying Parkinson’s genes could help explain what triggers the disease and one day lead to new treatments.

“There is good reason for optimism that these advances will be translated into direct benefits for our patients,” wrote Christine Klein and Andreas Ziegler of the University of Lubeck in Germany.

National Human Genome Research Institute

The pancreas is located in the abdomen behind the stomach. Islets

within the pancreas contain beta cells, which produce insulin.

Photo courtesy of NIDDK

Betheda, Md., 2010-2011 — A team led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), has captured the most comprehensive snapshot to date of DNA regions that regulate genes in human pancreatic islet cells, a subset of which produces insulin.

The study highlights the importance of genome regulatory sequences in human health and disease, particularly type 2 diabetes, which affects more than 20 million people in the United States and 200 million people worldwide. The findings appear Nov. 3 in Cell Metabolism.

“This study applies the power of epigenomics to a common disease with both inherited and environmental causes,” said NHGRI Scientific Director Daniel Kastner, M.D., Ph.D. “Epigenomic studies are exciting new avenues for genomic analysis, providing the opportunity to peer deeper into genome function, and giving rise to new insights about our genome’s adaptability and potential.”

Epigenomic research focuses on the mechanisms that regulate the expression of genes in the human genome. Genetic information is written in the chemical language of DNA, a long molecule of nucleic acid wound around specialized proteins called histones. Together, they constitute chromatin, the DNA-protein complex that forms chromosomes during cell division. The researchers used DNA sequencing technology to search the chromatin of islet cells for specific histone modifications and other signals marking regulatory DNA. Computational analysis of the large amounts of DNA sequence data generated in this study identified different classes of regulatory DNA.

“This study gives us an encyclopedia of regulatory elements in islet cells of the human pancreas that may be important for normal function and whose potential dysfunction can contribute to disease,” said senior author and NIH Director Francis S. Collins, M.D., Ph.D. “These elements represent an important component of the uncharted genetic underpinnings of type-2 diabetes that is outside of protein-coding genes.”

Among the results, the researchers detected about 18,000 promoters, which are regulatory sequences immediately adjacent to the start of genes. Promoters are like molecular on-off switches and more than one switch can control a gene. Several hundred of these were previously unknown and found to be highly active in the islet cells.

“Along the way, we also hit upon some unexpected but fascinating findings,” said co-lead author Praveen Sethupathy, Ph.D., NHGRI postdoctoral fellow. “For example, some of the most important regulatory DNA in the islet, involved in controlling hormones such as insulin, completely lacked typical histone modifications, suggesting an unconventional mode of gene regulation.”

The researchers also identified at least 34,000 distal regulatory elements, so called because they are farther away from the genes. Many of these were bunched together, suggesting they may cooperate to form regulatory modules. These modules may be unique to islets and play an important role in the maintenance of blood glucose levels.

“Genome-wide association studies have told us there are genetic differences between type 2 diabetic and non-diabetic individuals in specific regions of the genome, but substantial efforts are required to understand how these differences contribute to disease,” said co-lead author Michael Stitzel, Ph.D., NHGRI postdoctoral fellow. “Defining regulatory elements in human islets is a critical first step to understanding the molecular and biological effects for some of the genetic variants statistically associated with type 2 diabetes.”

The researchers also found that 50 single nucleotide polymorphisms, or genetic variants, associated with islet-related traits or diseases are located within or very close to non-promoter regulatory elements. Variants associated with type 2 diabetes are present in six such elements that function to boost gene activity. These results suggest that regulatory elements may be a key component to understanding the molecular defects that contribute to type 2 diabetes.

Genetic association data pertaining to diabetes or other measures of islet function continue to be generated. The catalog of islet regulatory elements generated in the study provides an openly accessible resource for anyone to reference and ask whether newly emerging, statistically-associated variants are falling within these regulatory elements. The raw data can be found at the National Center for Biotechnology Information’s Gene Expression Omnibus using accession number GSE23784.

“These findings represent important strides that were not possible just five years ago, but that are now realized with advances in genome sequencing technologies,” said NHGRI Director Eric D. Green, M.D., Ph.D. “The power of DNA sequencing is allowing us to go from studies of a few genes at a time to profiling the entire genome. The scale is tremendously expanded. ”

In addition to the NHGRI and the NIH Intramural Sequencing Center, researchers from Duke University, Durham, N.C. and the University of Michigan, Ann Arbor, contributed to the study.

Previously known as adult-onset, or non-insulin dependent diabetes mellitus, type 2 diabetes usually appears after age 40, often in overweight, sedentary people. However, a growing number of younger people — and even children — are developing the disease.

Diabetes is a major cause of heart disease and stroke in U.S. adults, as well as the most common cause of blindness, kidney failure and amputations not related to trauma. Type 2 diabetes is characterized by the resistance of target tissues to respond to insulin, which controls glucose levels in the blood. This leads to gradual failure of insulin-secreting cells in the pancreatic islets. For more information about diabetes, visit http://diabetes.niddk.nih.gov/index.htm.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website, www.genome.gov.

The National Institutes of Health —”The Nation’s Medical Research Agency” — includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more, visit www.nih.gov.

The New York Times, February 1, 2011, by Benedict Carey  —  Every year scientists report that watching the Super Bowl is somehow unhealthy, even dangerous. Large bowls of snacks encourage overeating. Traffic accidents may increase after the game, too.

This year, a study in the journal Clinical Cardiology released on Monday warns that a loss by the hometown team in the big game leads to “increased deaths in both men and women, and especially older patients.” One of the authors said in a press release that “stress reduction programs or certain medications might be appropriate in individual cases.”

Therapists in Wisconsin and Pennsylvania are prepared. Most have seen plenty of people who suffer from what could be called Football Attention Neurosis (F.A.N.), in their practices, in their living rooms, and sometimes in the mirror.

“The belief that these patients have is that the world will end if the Steelers — uh, I mean, their team loses,” said Mark Hogue, a psychologist at Northshore Psychological Associates in Erie, Pa., who owns a trunkload of Pittsburgh Steelers paraphernalia, including a Snuggie. “As a therapist, you need to take that fear seriously.”

“Many patients, it needs to be said, will be self-medicating,” said Ursula Bertrand, a psychologist in private practice in Green Bay, Wis. “This can be helpful, but in excess it can also make anxiety attacks more likely.”

The causes of those attacks are very specific to the fan’s team, experts said.

A patient with an attachment to, for instance, the Green Bay Packers may be especially symptomatic if he or she sees the team’s quarterback running unprotected with the ball, especially if that quarterback has suffered previous concussions. The same patient might also suffer heart palpitations “whenever the Packers go out to receive a punt,” said Bradley C. Riemann, director of the Obsessive-Compulsive Disorder Center and cognitive-behavioral therapy services at Rogers Hospital in Oconomowoc, Wis., who has tickets to the Super Bowl and often travels to follow the Packers.

In contrast, a patient with an attachment to, for example, the Steelers might experience stabs of panic whenever he or she sees the team’s offensive line try to protect its quarterback from a surging defense. “They’ve had so many injuries on the line that it can be very hard to watch” for the patient, said Sam Knapp, a psychologist in Harrisburg, Pa., who records every Steelers game and watches only the victories.

Clearly, there’s a need for guidelines to deal with such patients. The following are derived from years of observations in the field and conversations with hundreds of sufferers of F.A.N. No licensed professional had, or would have, anything to do with them. They are the therapy version of fantasy football.

However, unlike many medical interventions, you can try these at home.

Treatment Guidelines

Football Attention Neurosis

I. Establishing a Therapeutic Alliance (Pregame)

Patients often arrive on the couch well before kickoff, agitated and highly resistant to treatment. Proceed with care. Attempts at small talk or queries about their mental well-being may at first be met with an irritated stare, a gesture toward the flat screen and insensitive remarks like “Do you mind?” or “The game’s about to start, O.K.?”

This is the disorder talking, not the person.

It also provides an opportunity to establish trust, by sitting with the sufferer and his or her feelings. A strong alliance is essential going forward, because it is often the case that treatment will involve asking the patient to do things that may be frightening or profoundly uncomfortable, like sitting quietly with eyes open as an erratic kicker attempts a late field goal.

II. Evaluating the Severity of Impairment (First Half)

The severity of the disorder will usually reveal itself early in the first half of the football contest. Some patients will exhibit physical symptoms, including flushing, heart palpitations, chest pain, even a choking sensation, when their team chokes. Others may show psychological signs, like disorientation, a numbed trancelike state, or disordered vocalizations like “What the…,” “How in the name of…,” “Oh, lord, no.”

“Tell me that didn’t just happen!” is another characteristic rhetorical reaction to an undesired play in the contest, almost always followed by this remark: “I can’t watch this anymore.”

Caution: Do not approach patients in these moments. They are fragile and prone to hurling nearby objects, including mini-bagels, plastic cups, pigs in a blanket — even themselves, in extreme cases, to the floor.

The time to complete the assessment is during commercial breaks, which are frequent and lengthy. Be sure to determine the family history (sample question: “Was your mother buried in a Reggie White jersey?”) and to make a careful review of medications, including nutritional supplements, prescriptions and a rough count of the 40-ounce malt liquor cans arranged like a mini-Stonehenge around the couch.

III. Formulating a Treatment Plan (Halftime)

Patients ritually leap to their feet and disappear at halftime. This break allows the therapist time to develop an intervention for the second half, when symptoms are most severe and disabling. The goals of treatment are the same for all patients: to reduce anxiety, to eliminate avoidance behaviors, to soothe physical symptoms like sleep loss, chronic groaning and cursing at the TV and the pets. Yet each individual suffers at different times and for different reasons, and the treatment plan must be tailored accordingly.

IV. Administering Therapy (Second Half)

The first commercial break after the second-half kickoff is the time to explain to the patient that his or her suffering is rooted in cognitive misconstruals, automatic assumptions that do not stand up to scrutiny.

For example, beliefs like a player “always fumbles” or “never makes late kicks” or “couldn’t cover my grandmother” represents an overestimate of risk. Each player is competent; each has succeeded in the past; all could cover Grandma, even on a slippery field.

Likewise, the notion that world will end if the patient’s team loses — catastrophizing, as this sort of thinking is known — does not stand up to the evidence. Remind the patient: Life resumed after each previous loss that the team suffered. And, in time, taste returned to food, colors became visible, feeling returned to extremities.

Breathing exercises are highly recommended and become increasingly important as the football contest nears the fourth quarter, when events on the field are likely to prompt strong physiological reactions, like a pounding heart, hyperventilation, even dizziness. These internal cues, as they’re called, can escalate the feeling of panic, a self-reinforcing cycle resulting in groans and cries that can be frightening to small children, pets and sometimes neighbors.

In the final minutes of the game, be forewarned: Many patients will move beyond the reach of therapy. Their faces may change, their breathing appear to stop. Researchers have not determined whether this state is closer to Buddhist meditation or to the experience of freefall from an airplane. All that is known is that, once in it, patients will fall back on primal coping methods, behaviors learned in childhood within the cultural context of their family.

Like emitting screams. Or leaping in an animated way, as if the floor were on fire. Or falling on their back and moving their arms and legs like an overturned beetle, in celebratory fashion.

Important note to therapist: At this point, if you are rooting for the same team as the patient, it will not violate ethical standards to join in.

Read the paper….  http://onlinelibrary.wiley.com/doi/10.1002/clc.20876/pdf