Duke researchers finds new clues to how cancer spreads

Posted by Biomechanism 

Cancer cells circulating in the blood carry newly identified proteins that could be screened to improve prognostic tests and suggest targets for therapies, report scientists at the Duke Cancer Institute.

Building on current technologies that detect tumor cells circulating in blood, the Duke team was able to characterize these cells in a new way, illuminating how they may escape from the originating tumors and move to other locations in the body.

The circulating tumor components include proteins normally seen when embryonic stem cells begin to specialize and move through the body to develop organs such as the heart, bones and skin, the Duke scientists reported this month in the journal Molecular Cancer Research.

The discovery may enhance the accuracy of blood tests that detect circulating cancer cells, giving doctors better information to gauge how a patient’s disease is responding or progressing.

“By developing a better blood test based on our findings, we may be able to identify molecular targets for therapy tailored to an individual patient’s cancer,” said Andrew J. Armstrong, M.D., ScM, assistant professor of medicine at Duke and lead author of the study.

The Duke team isolated tumor cells from blood samples of 57 patients, including 41 men with advanced prostate cancer and 16 women with metastatic breast cancer.

In the tumor cells of more than 80 percent of the prostate cancer patients and 75 percent of those with breast cancer, the researchers detected a group of proteins normally seen during embryonic development when stem cells begin to assume distinct roles.

As stem cells morph to build tissue and organs, they switch back and forth in what is known as epithelial-mesenchymal transition (EMT) and it’s opposite, mesencymal-epithelial transition (MET). Cancer cells have that same ability, changing from an epithelial cell similar to the organs from which they arose, to a mesenchymal or connective tissue-like cell. This EMT may underlie much of the treatment resistance and ability of cancer cells to spread.

Current FDA-approved blood tests that detect circulating tumor cells flag molecules associated with epithelial transitions; however, the Duke team found additional markers associated with mesenchymal origins, adding new targets that could be used to enhance the usefulness and sensitivity of the tests.

“Cancer is a hijacking of that normal embryonic stem cell process,” Armstrong said. “It reactivates this silent program that is turned off in adult cells, allowing tumor cells to move throughout the body and become resistant to therapy.”

Armstrong said the involvement of EMT/MET processes in tumor growth is a relatively new finding that is gaining acceptance among cancer scientists. The discovery by the Duke team adds strong evidence that the EMT/MET processes are underway when a patient’s cancer is spreading.

“In my opinion this work presents some of the most compelling data for the existence of epithelial-mesenchymal transitions in human cancer,” said Mariano A. Garcia-Blanco, professor of medicine, molecular genetics and microbiology, and senior author in the work.

“This work should pave the way for studies to understand the mechanisms underlying these transitions in humans and their importance in disease progression and therapy,” said Garcia-Blanco, who is also director of the Duke Center for RNA Biology.

The Duke team additionally noted that tumor cells appear to be most dangerous when they can easily transition between EMT and MET in a stem cell-like phase of changability that enables them to grow, spread and resist treatment.

That finding could provide new opportunities for novel therapies that target these morphing mechanisms.

“This is not just for a biomarker, it’s a direction to take therapies as well,” Armstrong said. “It’s a new horizon.”

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In addition to Armstrong and Garcia-Blanco, study authors include Matthew S. Marengo; Sebastian Oltean; Gabor Kemeny; Rhonda L. Bitting; James Turnbull; Christina I. Herold; Paul K. Marcom; and Daniel George.

The study was funded with grants from the National Institutes of Health; the Department of Defense Prostate Cancer Research Program; the Prostate Cancer Foundation; the American Cancer Society; and the Duke Cancer Institute.

Armstrong, Oltean, George and Garcia-Blanco have a patent application for the biological process used for detecting the blood markers.

Insight into plant behavior could aid quest for efficient biofuels

Posted by Biomechanism 

Tiny seawater alga could hold the key to crops as a source of fuel and plants that can adapt to changing climates.

Researchers at the University of Edinburgh have found that the tiny organism has developed coping mechanisms for when its main food source is in short supply.

Understanding these processes will help scientists develop crops that can survive when nutrients are scarce and to grow high-yield plants for use as biofuels.

Green algae in seawater floating on the water surface in a creek. Credit: Biomechanism.com

The alga normally feeds by ingesting nitrogen from surrounding seawater but, when levels are low, it reduces its intake and instead absorbs other nutrients, such as carbon and phosphorus, from the water. The organism is also able to recycle nitrogen from its own body, breaking down proteins that are plentiful to make other proteins that it needs to survive.

Nitrogen is needed by all plants to survive but the alga’s survival strategies vary from most other plants which, when nitrogen is scarce, tend to widen their search for it.

Like many organisms, the alga – Ostreococcus tauri – is also driven by daylight and its body clock – for example, proteins that produce starch for food are active in the evening, after the plant has photosynthesised sugars from sunlight in the day.

The study, in the Journal of Proteomics, was funded by the Biotechnology and Biological Sciences Research Council and the Engineering and Physical Sciences Research Council.

Dr Sarah Martin, of the University of Edinburgh, who took part in the study, said: “This tiny alga certainly punches above its weight when it comes to survival. Our study has revealed some curious ways in which the organism finds the nutrients it needs to stay alive – tricks like these could be useful to us in developing sustainable crops for the future.”

More Information On Ostreococcus

Ostreococcus tauri strain OTH95, photo courtesy of Hervé Moreau, Laboratoire Arago

Ostreococcus belongs to the Prasinophyceae, an early-diverging class within the green plant lineage, and is reported as a globally abundant, single-celled alga thriving in the upper (illuminated) water column of the oceans. The most striking feature ofO. tauri and related species is their minimal cellular organization: a naked, nearly 1-micron cell, lacking flagella, with a single chloroplast and mitochondrion.

Three different ecotypes or potential species have been defined, based on their adaptation to light intensity. One (O. lucimarinus) is adapted to high light intensities and corresponds to surface-isolated strains. The second (RCC141) has been defined as low-light and includes strains from deeper in the water column. The third (O.tauri) corresponds to strains isolated from a coastal lagoon and can be considered light-polyvalent. Comparative analysis of Ostreococcus sp will help to understand niche differentiation in unicellular eukaryotes and evolution of genome size in eukaryotes.

According to Bioinformatics & Evolutionary Genomics in Belgium. Ostreococcus tauri is a unicellular green alga that was discovered in the Mediterranean Thau lagoon (France) in 1994. With a size less than 1 µm , comparable with the size of a bacterium, it is the smallest eukaryotic organism described until now.

Its cellular organisation is rather simple with a relative large nucleus with only one nuclear pore, a single chloroplast, one mitochondrion, one Golgi body and a very reduced cytoplasmatic compartment. The presence of only one chloroplast and mitochondrium makes it interesting to use not only for evolutionary studies, but also for experimental studies. Morphologically, the absence of flagella is the most typical characteristic of Ostreococcus tauri compared with other green algae.

Apart from this simple cellular structure, the genome size ofOstreococcus tauri is the smallest of all known eukaryotes. The nuclear genome is about 12 Mb, fragmented into 20 chromosomes, ranging in size from 120 to 1500 Kb. Phylogenetic analysis placed Ostreococcus tauri within the Prasinophyceae, an early branch of the Chlorophyta (green algae).

Scientists Measure Body Temperature of Dinosaurs for the First Time

Scientists Measure Body Temperature of Dinosaurs for the First Time

Posted by Biomechanism 

Some dinosaurs were as warm as modern mammals

Were dinosaurs slow and lumbering, or quick and agile?

It depends largely on whether they were cold- or warm-blooded.

Skull reconstruction of Camarasaurus; its body temperature was similar to that of humans. Credit: Sauriermuseum Aathal, Switzerland

When dinosaurs were first discovered in the mid-19th century, paleontologists thought they were plodding beasts that relied on their environment to keep warm, like modern-day reptiles.

But research during the last few decades suggests that they were faster creatures, nimble like the velociraptors or T. rexdepicted in the movie Jurassic Park, requiring warmer, regulated body temperatures.

Now, researchers, led by Robert Eagle of the California Institute of Technology, have developed a new way of determining the body temperatures of dinosaurs for the first time, providing new insights into whether dinosaurs were cold- or warm-blooded.

“Eagle and colleagues have applied the newest and most innovative techniques to answering the question of whether dinosaurs were warm- or cold-blooded,” says Lisa Boush, program director in the National Science Foundation’s (NSF) Division of Earth Sciences, which funded the research.

“The team has made important strides in discovering that the body temperature of dinosaurs was close to that of mammals, and that the dinosaurs’ physiology allowed them to regulate that temperature. The result has implications for our understanding of dinosaurs’ ecology–and demise.”

By analyzing the teeth of sauropods–long-tailed, long-necked dinosaurs that were the biggest land animals ever to have lived–the scientists found that these dinosaurs were about as warm as most modern mammals.

“This is like being able to stick a thermometer in an animal that has been extinct for 150 million years,” says Eagle, a geochemist at Caltech and lead author of a paper to be published online today in the journal Science Express.

“The consensus was that no one would ever measure dinosaur body temperatures, that it’s impossible to do,” says John Eiler, a co-author and geochemist at Caltech. But using a technique pioneered in Eiler’s lab, the team did just that.

Scientists at work unearthing dinosaur fossils at a site in Como Bluff Quarry, Wyoming. Credit: Melissa Connely, Wyoming Dinosaur International Society

The researchers analyzed 11 teeth, unearthed up in Tanzania, Wyoming and Oklahoma, that belonged to the dinosaurs Brachiosaurus and Camarasaurus.

They found that Brachiosaurus had a temperature of about 38.2 degrees Celsius (100.8 degrees Fahrenheit) and Camarasaurushad one of about 35.7 degrees Celsius (96.3 degrees Fahrenheit), warmer than modern and extinct crocodiles and alligators, but cooler than birds.

The measurements are accurate to within one or two degrees Celsius.

“Nobody has used this approach to look at dinosaur body temperatures before, so our study provides a completely different angle on the long-standing debate about dinosaur physiology,” Eagle says.

The fact that the temperatures were similar to those of most modern mammals might seem to imply that dinosaurs had a warm-blooded metabolism.

But, the researchers say, the issue is more complex. Because sauropod dinosaurs were so huge, they could retain their body heat much more efficiently than smaller mammals like humans.

“The body temperatures we’ve estimated provide key information that any model of dinosaur physiology has to be able to explain,” says Aradhna Tripati, a co-author who’s a geochemist at University of California, Los Angeles and visiting geochemist at Caltech. “As a result, the data can help scientists test physiological models to explain how these organisms lived.”

Close-up of a Camarasaurus skull, displaying its dentition with large spatulate teeth. Credit: Sauriermuseum Aathal, Switzerland

The measured temperatures are lower than what’s predicted by some models of dinosaur body temperatures, suggesting there is something missing in scientists’ understanding of dinosaur physiology.

These models imply that dinosaurs were so-called gigantotherms, that they maintained warm temperatures by their sheer size.

To explain the lower temperatures, the researchers suggest that dinosaurs could have had physiological or behavioral adaptations that allowed them to avoid getting too hot.

The dinosaurs could have had lower metabolic rates to reduce the amount of internal heat. They could also have had something like an air-sac system to dissipate heat.

Alternatively, they could have dispelled heat through their long necks and tails.

Previously, researchers have only been able to use indirect ways to gauge dinosaur metabolism or body temperatures.

For example, they inferred dinosaur behavior and physiology by figuring out how fast dinosaurs ran based on the spacing of dinosaur tracks, studying the ratio of predators to prey in the fossil record, or measuring the growth rates of bone.

But these lines of evidence were often in conflict.

“For any position you take, you can easily find counter-examples,” Eiler says. “How an organism budgets the energy supply it gets from food, and creates and stores the energy in its muscles–there are no fossil remains for that.”

Eagle, Eiler and colleagues developed what’s known as a clumped-isotope technique that shows that it’s possible to determine accurate body temperatures of dinosaurs.

“We’re getting at body temperature through a line of reasoning that I think is relatively bullet-proof, provided you can find well-preserved samples,” Eiler says.

Sideview of a Camarasaurus skeleton still in sandstone, found on Howe Ranch, Wyoming. Credit: Sauriermuseum Aathal, Switzerland

In this method, the researchers measured the concentrations of the rare isotopes carbon-13 and oxygen-18 in bioapatite, a mineral found in teeth and bone.

How often these isotopes bond with each other–or “clump”–depends on temperature.

The lower the temperature, the more carbon-13 and oxygen-18 bond in bioapatite. Measuring the clumping of these isotopes is a direct way to determine the temperature of the environment in which the mineral formed–in this case, inside the dinosaur.

“What we’re doing is special in that it’s thermodynamically-based,” Eiler says. “Thermodynamics, like the laws of gravity, is independent of setting, time and context.”

Because thermodynamics worked the same way 150 million years ago as it does today, measuring isotope clumping is a reliable technique, says Eiler.

Identifying the most well-preserved samples of dinosaur teeth was one of the major challenges of the analysis.

The scientists used several ways of finding the best samples. For example, they compared the isotopic compositions of resistant parts of teeth–the enamel–with easily altered materials like the fossil bones of related animals.

The next step, the researchers say, is to determine the temperatures of more dinosaur samples, and extend the study to other species of extinct vertebrates.

In particular, discovering the temperatures of unusually small and young dinosaurs would help test whether dinosaurs were indeed gigantotherms.

Knowing the body temperatures of more dinosaurs and other extinct animals would also allow scientists to learn more about how the physiology of modern mammals and birds evolved.

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In addition to Eagle, Eiler and Tripati, co-authors of the paper are Thomas Tütken from the University of Bonn, Germany; Caltech undergraduate Taylor Martin; Henry Fricke from Colorado College; Melissa Connely from the Tate Geological Museum in Casper, Wyoming; and Richard Cifelli from the University of Oklahoma. Eagle also has a research affiliation with UCLA.

The research was also supported by the German Research Foundation.