Mayo Clinic cancer researchers have discovered a key partnership between two genes in mice that prevents the development of cancer of the lymph nodes, known as T-cell leukemia or lymphoma.

This first-time finding provides researchers with a promising target for designing new anti-cancer drugs that fight lymphomas, as well as other cancers in which this partnership exists, including breast and colon cancers.

The Mayo Clinic research report appears as the cover story in today’s edition of the journal, Cancer Cell, (http://www.cancercell.org). Jan van Deursen, Ph.D., a specialist in pediatric cancers with the Department of Pediatrics and a member of the Mayo Clinic Cancer Center, led the research team.

According to Dr. van Deursen, the Mayo Clinic cancer research team used specially-bred laboratory mice to demonstrate three things not previously known about the development of these types of cancer. They are the first to:

* Provide laboratory evidence that the gene CBP is a tumor suppressor — and that the lack of CBP contributes to the formation of lymphoma.

* Demonstrate that the absence of CBP works in partnership with low levels of a protein called p27Kip1. When these two conditions are present, lymphoma development accelerates in mice.

* Discover that two compounds — Cyclin E and Skp2 — control p27Kip1 levels.

“We not only found the tumor suppressor, we also showed what other gene defects need to occur in the same cell for cancer to progress,” says Dr. van Deursen. “Cancer is not the result of a single defect, but is related to a combination of defects and events,” he explains. “To find the best treatment, it’s vital to discover what combinations of changes have occurred with the cell to transform it from a normal cell into a cancer cell.” Lymphoma belongs to the hematologic malignancies group of cancers because it involves blood, bone marrow and lymph nodes. In general, it is one of the more common cancers and it is increasing in the United States. Each year about 50,000 Americans are diagnosed with some form of lymphoma, and another 30,000 die from the cancer.

Background Analogy: Cancer as a River and the Search for its Headwaters

Cancer researchers liken cancer to a river with directional flow. Like a river, cancer flows downstream toward production of disease. What researchers want to find is the upstream headwaters — the point of origin that eventually leads to cancer.

They look for the earliest “upstream” cellular irregularities that contribute to dangerous “downstream” conditions. In this study, Mayo Clinic researchers discovered a previously unknown early, upstream event in the cancer process — that the compounds Cyclin E and Skp2 are upstream elements that control the downstream level of p27Kip1. They found that when p27Kip1 levels are low, and when combined with the absence of CBP, conditions favor cancer.

“Low levels of p27Kip1 are often associated with human cancers and with very poor prognosis,” says Dr. van Deursen. “We have shown in our research the mechanism by which p27Kip1 gets altered. Now that we know this mechanism, we can design treatments to keep levels of p27Kip1 from going down.”

Dr. van Deursen notes that altered levels of p27Kip1 are not the result of a defective gene. Rather, the altered levels are the indirect result of high levels of the upstream molecules, Cyclin E and Skp2.

“If we can prevent these indirect upstream effects from happening, then the undesirable downstream events will not occur,” he says.

From this finding, the Mayo Clinic cancer researchers conclude that a cooperative relationship exists between the loss of CBP and depressed levels of p27Kip1 to produce cancer.

A grant to Mayo Clinic from the Department of Defense funded this research study. Researchers from St. Jude Children’s Research Hospital in Memphis, Tenn., also contributed to the investigation.

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It wouldn’t have been the easiest way to get around. A University of Alberta paleontologist has helped discover the existence of a 95 million-year-old snakelike marine animal, a finding that provides not only the earliest example of limbloss in lizards but the first example of limbloss in an aquatic lizard.

Close-up of Adriosaurus microbrachis.

A University of Alberta paleontologist has helped discover the existence of a 95 million-year-old snakelike marine animal, a finding that provides not only the earliest example of limbloss in lizards but the first example of limbloss in an aquatic lizard.

“This was unsuspected,” said Dr. Michael Caldwell, from the U of A’s Faculty of Science. “It adds to the picture we have of what was happening 100 million years ago. We now know that losing limbs isn’t a new thing and that lizards were doing it much earlier than we originally thought. On top of that, this lizard is aquatic. All the examples we have in our modern world are terrestrial, so it’s a big deal.”

The evidence offers the earliest record of vestigial limbs–once used in an animal’s evolutionary past but that has lost its original function– in a fossil lizard. The newly named species–Adriosaurus microbrachis–is described in the current issue of the Journal of Vertebrate Paleontology and offers clues to the evolution of terrestrial lizards as they returned to water.

The fossil was originally collected during the 19th Century from a limestone quarry in Slovenia. It then sat at the Natural History Museum in Trieste, Italy for almost 100 years before Caldwell and a colleague found it in 1996 during a trip to Europe. He later connected with Alessandro Palci, then a graduate student in Italy whom he helped supervise, and they worked on the fossil together.

The researchers soon realized the lizard’s front limbs were not formed during development. “There was a moment when I said, ‘I think we stumbled on a new fossil illustrating some portion of the aquatic process of losing limbs,’” said Caldwell. “There are lots of living lizards that love to lose their forelimbs and then their rearlimbs, but we didn’t know it was being done 100 million years ago and we didn’t know that it was happening among groups of marine lizards.”

The researchers think this snake-like lizard was about 10 to 12 inches long, had a small head perched on an elongated neck, body and tail and relatively large and well-developed rear limbs. All bones of the forearm, including the hands and digits were not formed during development.

“For some oddball reason the forelimbs were lost before the rear limbs when you would think it would be the opposite,” said Caldwell. “The front limbs would be useful for holding onto dinner or digging a hole but it must be developmentally easier to get rid of the forelimbs.”

The most well known ancient fossil snakes also kept their hind limbs. Living lizards also show almost every variation in limb reduction from a perfectly formed back limb with no forelimb, or a spike for a forelimb and one or two toes on the rearlimb, to total limblessness. This degree of variation makes it very difficult to understand the pattern of evolutionary limb loss in these animals.

“This discovery is one more data point that might help us answer some questions and perhaps shed some light on the fin to limb transition, which is a key step in the evolution of land animals,” said Caldwell. “It doesn’t give us all the answers but it’s a start.”

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A research team led by San Jose State University and the University of California, Santa Barbara has discovered forests of a species of kelp previously thought endangered or extinct in deep waters near the Galapagos Islands.

Marine iguana feeding in area of kelp forest.

The discovery has important implications for biodiversity and the resilience of tropical marine systems to climate change.

“The ecosystems that form in these cold, deep pockets beneath warm tropical waters look more like their cousins in California than the tropical reefs just 200 feet above,” said co-author Brian Kinlan, a researcher with UC Santa Barbara’s Marine Science Institute. “It is very similar to what we see when we climb a high mountain. For example, high alpine country in California looks more like Alaska.”

Kinlan and Michael Graham, associate professor at SJSU, began by developing a mathematical model designed to predict likely habitat for the kelp, Eisenia galapagensis, based on information from satellites and oceanographic instruments on conditions including light, depth and nutrient availability. The premise of the model was developed by collaborator Louis Druehl, of the Bamfield Marine Science Centre, who surmised it was possible to create a predictive model for locating kelp forests rather than focusing on the limited details available from rare field observations.

The research team tested the model by traveling to the predicted habitat, where they searched for the kelp. Scuba divers — including students from CSU Monterey Bay, CSU East Bay and UC Davis — found the kelp forests from 40 to 200 feet below the surface, making the mission a success. The students conducted their surveys alongside the famed Amblyrhynchus christatus, the world’s only seagoing iguanas.

The mission’s success has three major implications. First, the World Conservation Union, which recently added Eisenia galapagensis to its global database of threatened species, may reconsider that action. Second, the model may find other marine life presumed endangered or rare but actually hidden beneath the ocean’s surface.

The model does this by pinpointing unexpected places to search. In this case, the model correctly predicted that deep waters in the tropics could harbor kelp forests more commonly associated with temperate regions such as central California. The model identified nearly 10,000 square miles of similar unexpected cold spots in deep tropical waters worldwide.

The third implication of the research is that marine biodiversity may be more tolerant of climate change than presumed. Graham compares his team’s kelp forests to the underwater hydrothermal vents discovered off South Africa in 1977. Scientists were surprised to find thriving ecosystems near those vents in water previously considered too deep and dark to harbor complex communities.

Graham theorizes the kelp forests his team discovered may reveal a similar wealth of plant and animal life. So while global warming may heat coral reefs and alter life there, marine communities may continue to thrive in kelp forests deep beneath the surface, where cooler nutrient-rich waters are less affected by surface warming.

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