It may become possible for biomarkers in blood to reveal whether mutated cells have turned a corner toward forming tumors, and how long the process — depending on the type of cancer — is likely to take. That could give patients a sense of the risk they face before they become ill.

Rice chemist Anatoly Kolomeisky, with postdoctoral research associate Hamid Teimouri and graduate alumna Maria Kochugaeva, directed their theoretical expertise in modeling random (stochastic) processes to the problem of why cancerous cells that are usually destroyed by the body’s immune system sometimes overcome a gauntlet of defenses to become tumors.

The study in Scientific Reports is intended to clarify microscopic aspects of cancer initiation, the point at which random mutations become “fixed” in cells, which pass them on and eventually overwhelm tissue.

As part of their study, the researchers calculated fixation probabilities for 28 types of cancer to see how they correlate with available clinical data on cancer lifetime risks — and found that correlation was anything but sure.

“The problem with cancer is that we’re detecting it too late,” said Kolomeisky, a professor of chemistry and chairman of the department in Rice’s Wiess School of Natural Sciences. The researchers argue their “convenient, simple and versatile” method to evaluate cancer initiation dynamics should incorporate initiation dynamics for specific cancer types as well as established lifetime risks.

Kolomeisky has a long track record of discovery related to cellular mechanisms, especially related to motor proteins that transport cargo in cells and genome editing. Inspired by an off-hand comment from a colleague that his calculations looked like they could relate to cancer, Kolomeisky set off to find out if his mathematical approach could be applied to cancer initiation dynamics.

Based on their formulas, the researchers developed a chart correlating lifetime risks and initiation times for 28 types of cancer — and found very little to connect the two. “It indicates that cancer lifetime risks alone cannot be utilized to evaluate the danger of getting cancer,” the researchers wrote, suggesting fixation times that indicate tumor initiation are a more important metric.

For example, the chart shows that colorectal adenocarcinoma with FAP carries the highest lifetime risk, but its fixation time of 15 years is nearly three times that of duodenum adenocarcinoma with FAP, which is thought to have a much lower lifetime risk. At the other end of the fixation scale are hepatocellular carcinomas, at more than 31,000 years.

Their calculations compared the “fitness” of individual cells with cancer-related mutations to normal cells without, and how fast they divided. Tissue with mutant cells that divided at a 1-to-1 ratio with normal cells were the slowest to “fix” tumors.

The researchers assumed mutant cells with a speed advantage would fix tumors faster, and they were right. But they were surprised when their models showed cells with disadvantageous mutations (slower-than-normal division) were also occasionally faster than normal cells to fix.

“People assume, usually subconsciously, that something more probable will happen faster,” Kolomeisky said. “But we found that is not the case for cancers. Doctors shouldn’t make decisions simply on lifetime risk, as is typically done, but also on the dynamics we calculated as our main results.

“The main points are that we can calculate, with a lot of assumptions, the average time before cancer will start,” he said. “We also argue that the probability of cancer does not typically correlate well with the time it starts. Something more probable is not necessarily fast.”

Mutant cells that release biomarkers to the bloodstream may provide a better way to spot precancerous conditions.

“In the future, this could become part of personalized medicine,” Kolomeisky said. “A doctor gives you a test and checks for the fraction of mutated cells in your tissues.

Then you can estimate how long it would take before the mutated cells will occupy the whole tissue. If it’s 100 years, you probably should not worry too much. But if it’s one year, then you might have to take drastic measures.”

He said the model will certainly improve as more relevant parameters are incorporated. But anything it produces now and in the future should not deter one from a healthy lifestyle.

“We’re not saying that you will or won’t get cancer no matter what you do,” Kolomeisky said. “Just that the probability is different. If you smoke, if you don’t eat well or don’t exercise, the probability will be higher.”

Published in the Journal of Neuroscience, this research pinpoints a specific neural circuit that when altered caused animal models to drink less alcohol.

“The fact that these neurons promote reward-like behavior, that extremely low levels of alcohol consumption activate these cells, and that activation of these neurons drive alcohol drinking in animals without extensive prior drinking experience suggests that they may be important for early alcohol use and reward,” said senior author Zoe McElligott, PhD, assistant professor of psychiatry and pharmacology. “It’s our hope that by understanding the function of this circuit, we can better predict what happens in the brains of people who transition from casual alcohol use to subsequent abuse of alcohol, and the development of alcohol use disorders.”

McElligott, who is also a member of the UNC Bowles Center for Alcohol Studies, set out to investigate if a population of neurons that express a specific neuropeptide (neurotensin or NTS) contributes to reward-like behaviors and alcohol drinking. She was especially interested in these neurons in the context of inexperienced alcohol use, such as when a person first begins to drink alcohol. Also, NTS neurons are a subpopulation of other neurons in this CeA brain region that have been implicated in anxiety and fear — known as the somatostatin and corticotropin releasing factor neurons.

Using modern genetic and viral technologies in male mice, McElligott and colleagues found that selectively lesioning or ablating the NTS neurons in the CeA, while maintaining other types of CeA neurons, would cause the animals to drink less alcohol. This manipulation did not alter anxiety-like behavior. It also did not affect the consumption of other palatable liquids such as sucrose, saccharin, and bitter quinine solutions.

“We found that these NTS neurons in the CeA send a strong projection to the hindbrain, where they inhibit the parabrachial nucleus, near the brainstem,” McElligott said.

Using optogenetics — a technique where light activates these neurons — the researchers stimulated the terminal projections of the CeA-NTS neurons in the parabrachial and found that this stimulation inhibited the neurons in the parabrachial. When the scientists stimulated this projection with a laser in one half of the animal’s box, animals would spend more time where the stimulation would occur.

Animals also learned to perform a task to get the laser stimulation to turn on, and they would do this repeatedly, suggesting that they found this stimulation to be rewarding.

“Furthermore, when we stimulated this projection, animals would drink more alcohol as compared to when they had an opportunity to drink alcohol without laser stimulation,” McElligott said. “In contrast to our study where we ablated the NTS neurons, laser stimulation of this parabrachial pathway also caused the animals to consume caloric and non-caloric sweetened beverages. When the animals were presented with regular food and a sweet food, however, laser stimulation did not enhance the consumption regardless of the mouse’s hunger state. This suggests that different circuits may regulate the consumption of rewarding fluids and solids.”

McElligott and her graduate student María Luisa Torruella Suarez, the first author of this study, hope to explore how alcohol experience may change these neurons over time.

“Would these cells respond differently after animals have been drinking high quantities of alcohol over time?” McElligott said. “We also want to discover which populations of neurons in the parabrachial are receiving inputs from these neurons. Fully understanding this circuit could be the key to developing therapeutics to help people with alcohol use disorders.”

The National Institutes of Health, The North Carolina Translational Clinical Science (NC TraCS) Institute, the Alcohol Beverage Medical Research Foundation, and The UNC Bowles Center for Alcohol Studies funded this research.

The research, which appears online on December 11 in the journal Environmental Science and Technology, could point toward ways to mitigate the worst effects of mercury poisoning in regions such as those that are already experiencing elevated mercury levels caused by gold mining.

“We’ve taken a lot of ground measurements in the Peruvian Amazon of mercury levels in the water, soil and fish,” said Heileen Hsu-Kim, professor of civil and environmental engineering at Duke University. “But many areas in the Amazon aren’t easily accessible, and the government often does not have the resources needed to test local sites.”

“When you clear the land for mining, it leaves behind a landscape that basically went from lush greenery to barren desert,” said Hsu-Kim. “You can easily see the effects in satellite images. If (governments) could use publicly available satellite imagery to identify areas that are likely to be contaminated, it could help them make informed policy decisions to protect public health.”

The past two decades have seen a sharp increase in illegal and informal gold mining in Peru’s southern Amazon region of Madre de Dios. These small-scale operations typically involve cutting down all of the trees in a particular area, digging a large pit and then using mercury to extract gold from the excavated soil.

After larger, coarse particles are separated, the remaining fine soil is combined with water and mercury inside a large drum much like an oil barrel, and shaken. The mercury binds to any gold in the soil, creating a large chunk that can be easily removed. This chunk is then burned, evaporating and releasing the mercury into the air while leaving behind pure gold.

Besides releasing mercury into the atmosphere, miners typically add three to four times more mercury to each barrel than is actually needed, says Hsu-Kim. While this ensures all of the gold is extracted, it also means there is a large amount of leftover mercury in the slurry that is inevitably dumped back into the excavated pit.

And because the whole process started with the clearing of trees, there’s nothing to stop the mercury-laden soil from eroding into nearby rivers.

“While the local mercury levels might only double due to the mining itself, the effect of the erosion creates a four-fold increase in the amount of mercury being released into local rivers,” said Hsu-Kim.

“This means mining practices can hit people three times with mercury — once from direct contact, once from atmospheric transport and deposition, and once from soil mercury mobilization due to land clearing,” said William Pan, the Elizabeth Brooks Reid and Whitelaw Reid Associate Professor of Population Studies at Duke. “The scenarios we run demonstrate that even if mining were to end today, since vegetation is unlikely to return for several decades, the cleared land will continue to release mercury.”

Hsu-Kim and Pan worked with graduate students Sarah Diringer and Axel Berky to build a model to predict the amount of mercury and other contaminants being released into rivers. It combines data from a watershed erosion model, local variables such as annual rainfall, landscape and soil types, and data gathered about deforestation from satellite imagery.

When they analyzed mercury content in samples of soil and water from nine locations in the Colorado River watershed in Madre de Dios, they found that their model accurately predicted which areas were likely to have higher water concentrations of mercury.

The model suggests that over the last two decades, deforestation has doubled the amount of mercury entering local water sources in the Colorado River watershed, and increased it four-fold in the Puquiri subwatershed. Their model also suggests that if the current trends of deforestation continue, the amount of mercury being released into the local river systems may increase by 20 to 25 percent by 2030.

While the findings may sound bleak, the fact that the model works does offer some light at the end of the tunnel.

“We have shared our model with the Peruvian Ministry of Environment and Ministry of Health,” Pan said. “We are working with them to evaluate whether our approach can be used as a tool for developing new policies regarding mining, environmental monitoring of mercury and human exposure.”

Story Source:

Materials provided by Duke University. Original written by Ken Kingery. Note: Content may be edited for style and length.