A clinical trial for a new technology to diagnose and treat prostate cancer marks the first time Purdue University has directed the entire pathway of a therapeutic product from early research to patient treatment.
Therapeutics developed from research at the university are typically licensed to a pharmaceutical
company that takes it through the pipeline of preclinical studies, manufacturing and then clinical trials, said Timothy Ratliff, the Robert Wallace Miller Director of the Purdue University Center for Cancer Research who is leading the project.
“Purdue has a long history of research that has been the basis of life-saving treatments, and now we’ve shown that we can take a therapeutic drug or technology through every step from concept to clinical trial,” Ratliff said. “By managing the process all the way through to a clinical trial, the scientists behind the advancement maintain control of its development as it goes through the trials and get the satisfaction of seeing their discovery impact patients and improve lives.”
Eventually most therapeutic treatments developed at Purdue will have to be sold to a company in order to be manufactured and widely distributed. The further along in the process a product is, the better it is for the university and the state, he said.
“The value of a potential treatment increases as it makes its way through each step of the process, which means the scientists and the university will receive more revenue to continue the research process,” he said. “Managing the design, development and testing also means more money stays in the state and more Indiana workers are involved in the process.”
The ongoing clinical trial is testing the combination of a radioimaging agent and a prostate cancer-targeting molecule developed by Philip Low, Purdue’s Ralph C. Corley Distinguished Professor of Chemistry.
Low and his research team designed a targeting molecule that seeks out and attaches to prostate-specific membrane antigen, or PSMA, a protein that is found on the outer membrane of the cells of more than 90 percent of all prostate cancers.
“The targeting molecule is in essence a homing device for prostate cancer that can link to a variety of therapeutic agents, including imaging agents and drugs,” said Low, who also is a member of the Purdue Center for Cancer Research. “PSMA acts as the homing signal for the molecule, which binds to the protein and then is carried inside the cancer cell. The molecule and its cargo go only to cancerous tissue and leave healthy tissue unharmed.”
Ratliff and Low are working with scientists and physicians at the Indiana University School of Medicine and the Indiana University Melvin and Bren Simon Cancer Center to perform the clinical trial.
The clinical trial is the first to test the technology in humans and will evaluate the targeting molecule’s ability to recognize prostate cancer and deliver an imaging agent. The patients included in the study have prostate cancer that can be seen by computerized tomography scan, or CT scan, so that it can easily be determined how well the radioimaging agent is reaching the cancerous tissue.
“If the new technology picks up the cancer that we know and can see, we will have more confidence that it can also pick up cancer that can’t be seen by a CT scan,” Low said. “If the trial goes well, we will begin a new imaging trial to determine if we can image prostate cancer well enough to help physicians stage the disease.”
Dr. Thomas Gardner, the urologist at the Indiana University Melvin and Bren Simon Cancer Center who treats the patients involved in the trial, said the technology may help reduce unnecessary procedures and allow other treatments to be given earlier.
“Treatment of prostate cancer depends on how far we think the disease has progressed, or its stage,” Gardner said. “If the cancer is confined to the prostate, we aggressively treat the organ itself, but if it has spread beyond the prostate a more systemic approach is necessary. It doesn’t make sense to put someone through focused treatments of their prostate and the side effects that go along with it if they will need to go through systemic treatments. Better detection would allow physicians to know that the cancer had spread at a much earlier point.”
There is currently only one radioimaging agent for prostate cancer approved by the Food and Drug Administration.
“The current imaging capabilities available for prostate cancer are very poor,” Low said. “The existing imaging agent is limited because of its large size, which is difficult to get into a solid tumor. Also, it seeks out a target located inside the cancer cell, so it is only able to mark injured cells that are falling apart as opposed to actively growing cancer cells.”
The targeting molecule and radioimaging agent combination designed by Low’s group is more than 150 times smaller than the existing agent and can much more easily penetrate a solid tumor to reach all of the cells inside, he said.
Three patients currently have been treated in the clinical trial that will include around 25 patients. The trial should be complete in about a year, Low said.
Dr. Song-Chu Ko, in the Department of Radiation Oncology at the IU School of Medicine and a member of the IU Melvin and Bren Simon Cancer Center, leads the clinical trial. In addition to Gardner and Ko, the IU team also includes Noah Hahn of the Department of Hematology and Oncology, Peter Johnstone of the Department of Radiation Oncology, James Fletcher of the Department of Nuclear Medicine, Michael Koch of the Department of Urology and Gary Hutchins of the Department of Radiology.
The chemically cleared leaf of Heteromeles arbutifolia shows its major and minor veins.(Credit: Christine Scoffoni/UCLA Ecology and Evolutionary Biology)
The size of leaves can vary by a factor of 1,000 across plant species, but until now, the reason why has remained a mystery. A new study by an international team of scientists led by UCLA life scientists goes a long way toward solving it.
In research federally funded by the National Science Foundation, the biologists found that smaller leaves are structurally and physiologically better adapted to dry soil because of their distinct vein systems.
The research will be published in an upcoming print issue of the journal Plant Physiology and is currently available in the journal’s online edition.
“A hike in dry areas, such as the Santa Monica Mountains, proves that leaves can be small. But if you are in the tropical forest, many leaves are enormous,” said Lawren Sack, a UCLA professor of ecology and evolutionary biology and senior author of the research.
This biogeographic trend — smaller leaves in drier areas — may be the best recognized in plant ecology, true at both the local and global scales, but it had evaded direct explanation, Sack said.
Sack and his research team focused on deciphering the meaning of the huge diversity in the patterns of veins across plants. They found that small leaves’ major veins — those you can see with the naked eye — are spaced more closely together and are of greater length, relative to the leaf’s size, than those of larger leaves.
This redundancy of major veins, the researchers say, protects the leaves from the effects of embolism — bubbles that form in their “water pipes” during drought — because it provides alternate routes for water to flow around vein blockages.
“Even with strong drought that forms embolism in the veins, a small leaf maintains function in its vein system and can keep functioning for water transport,” Sack said.
“Unlike people, plants don’t seem to have a complex hierarchy of needs — give them sun, water and nutrients, and they will be happy,” said Christine Scoffoni, a UCLA doctoral student in the department of ecology and evolutionary biology and lead author of the research. “But when one of these three fundamental resources becomes scarce, the plant will have to find a way to cope with it or die, because there is no escape. Coping with drought can be a strong selective factor on leaf form, especially on size and their venation.”
“When we ask our students in plant physiology class why plants need water, their first answer is for growth,” Sack said. “They are amazed to learn that the bulk of the water used by a plant is actually to make up for the water lost through transpiration, which would otherwise dry out the leaves. When the leaves open the small pores on their surface, the stomata, to capture carbon dioxide for photosynthesis, water is lost to the dry atmosphere. To stay moist inside, the plants need to replace the water lost by evaporation.”
To do this, plants need to maintain the continuity of water in their “pipe delivery system,” even as water is being pulled up by the leaves to replace water that has been lost to the air. This places tension on the water in the pipe system, known as the xylem, which runs through the roots and stem and into the leaf veins. And that continuity is challenged by dry soil, Sack explained.
“The less water in the soil, the more the leaves have to pull to get some out, so stronger tension starts building in the plant’s pipes,” Scoffoni said. “At a certain level of tension, an air bubble is pulled in from outside, blocking the flow of water. One way for a plant to withstand drought is to tolerate many of these embolisms.”
Having more major vein routes by which water can flow around the air bubble provides this ability. Smaller leaves, possessing more major veins spaced closely together in a given square centimeter, have this ability, Sack said.
To test this idea, the UCLA team collaborated with professor Hervé Cochard from France’s University of Clermont-Ferrand and a member of the Institut National de Recherche Agronomique, to construct three-dimensional computer models of leaves’ venation systems. They then simulated the impact of embolism on water transport for leaves of different sizes and vein architectures.
The biologists found a distinct difference in function between the major veins, which tend to show a branching pattern, and the minor veins, which form a grid embedded within the leaf and make up most of the leaf’s total vein length. Blocking the major veins had a huge impact on leaf function — but one that could be remedied by having additional, redundant major veins.
Scoffoni likens the major veins to a superhighway and the minor veins to sinuous city roads, where embolism is like an accident causing a major slowdown.
“If an air bubble forms in the leaf’s water pathway, the more alternate highways the vein system has to offer, the less the leaf will be affected by these accidents,” Scoffoni said.
The UCLA biologists — including co-authors Michael Rawls, an undergraduate student, and Athena McKown, a postdoctoral scholar in ecology and evolutionary biology — tested diverse leaves from very wet and dry areas, all planted near the UCLA campus. The leaves fit the pattern: The biologists found that smaller leaves indeed had more tightly packed major veins and were more resistant to the effects of embolism in the major veins. The were better able to maintain water transport, even during extreme drying, Sack said.
While the trend of smaller leaves in drier areas is so striking that it appears in textbooks, and the trend is used by scientists to estimate rainfall in the distant past from the size of fossil leaves, the mechanism had never been explained. The previous theory proposed an indirect linkage, arguing that smaller leaves have a thinner layer of still air around them, which allows them to cool off faster in hotter places. According to this theory, because many dry places are also warmer, this might lead to the evolution of smaller leaves in such environments.
As Sack noted, however, “this is indirect and does not explain the trend of smaller leaves in drier places when temperature is similar. This trend appears across species, and even within individual species, when plants are grown in moister and drier soil.”
The team expects that this mechanism, which points to a new role of vein architecture and leaf size in drought tolerance, will generate new interest in plant diversity and adaptation to environments. In addition, Sack said, the discovery shows that even very well-known biogeographic trends are open to new scientific explanation.
There are important lessons to be learned in the United States from the recent eruption of foodborne illness in Germany — which has turned out to be the deadliest E. coli outbreak ever — according to a food-safety expert in Penn State’s College of Agricultural Sciences.
More than 3,300 people have been sickened since the outbreak began, including nearly 800 with a serious complication that can lead to kidney failure and death. German health officials finally were able to trace the illness back to bean sprouts grown on a farm in northern Germany, but not before at least 39 people died.
Not all strains of E.coli are harmful. However, the strain that has caused the German outbreak is very pathogenic. (Credit: Penn State)
It’s a sobering example of how vital it is for health officials to be able to trace food back to its origin on the farm when an outbreak of foodborne illness occurs, said Luke LaBorde, associate professor of food science. LaBorde conducts extension programs that train farmers to use “good agricultural practices” (GAPs) aimed at preventing contamination in products such as sprouts, lettuce, tomatoes and cucumbers.
“The German officials simply were not able to trace the outbreak back quickly enough to determine where it started and what food was involved,” he said. “That’s why so many people got sick.”
“The seeds that producers buy for growing sprouts can be contaminated without any indication that they are unsafe to use,” he said. “So they are just going to continue using that seed until someone tells them, ‘Hey, that is making people sick.'”
LaBorde said the new federal food-safety law recently adopted in this country contains provisions that will enable scientists and government food-safety agencies to quickly trace foods back to their origins on the farm.
Now, every package or container of produce must include information about where a food product was grown or created. And because contamination can happen in processing, transport and storage, information about those also are logged and preserved, LaBorde pointed out.
In retrospect, he’s not surprised that sprouts were determined to be the cause of the German E. coli outbreak. “We’ve known for a long time that sprouts can be a problem,” he said. “The seeds may become contaminated by bacteria in animal manure in the field or during post-harvest storage.”
The process used to germinate seeds is ideal for growing pathogens, LaBorde added. “Abundant nutrients are present, along with high levels of moisture — and the warm temperatures needed for the sprouting process help to ensure survival and growth of bacteria,” he said.
“Mishandling of sprouts during production, packing or distribution has rarely been implicated as the source of sprout contamination. However, bacteria already present in the sprouting seed can continue to thrive if proper food-handling techniques are not practiced during harvest, processing and preparation.”
In the United States, the seeds usually are pre-treated with concentrated bleach solutions, and wash water that flows through the sprouts is collected and tested for bacteria such as E. coli, LaBorde explained.
“Perhaps that has not been done in Germany,” he said. “Increasingly in this country, we are testing irrigation water and wash water for contamination. There typically is a lot more surveillance here.”
LaBorde noted that increasing government testing and regulation is controversial in some circles because it adds costs and makes food more expensive, but politics and food safety aren’t compatible when people start getting sick due to foodborne illness.
“There was all sorts of hysteria before the new federal food-safety law came out about how small farmers would be unable to come up with new systems to handle the testing and reporting it required — record keeping was a real concern,” he said.
“And so there were some exceptions put into the bill that exempted growers with less than $500,000 in sales who sell direct to consumers or food stores.”
But regulation is a moot point in the marketplace, LaBorde contended, because food safety has been pushed onto the buyers. Each buyer — such as a huge supermarket chain — has their own standards that they impose on producers, and they are getting tougher and tougher. Small farmers and huge operations alike must abide by them.
“The private companies are way ahead of the government, and many now are requiring a third-party inspection of produce,” he said. “There are no politics in the private food industry — it is the bottom line that drives things.
“The large grocery store companies have simply decided they don’t want to deal with multimillion-dollar lawsuits against them involving contaminated foods. So they are requiring suppliers to put into place processes, tests and requirements — such as produce being GAPs certified — that guard against pathogens being present in their products.”
But LaBorde advises people to be aware that sprouts are just inherently more risky. “Even the Food and Drug Administration has said you can soak sprouts in bleach and still not kill every pathogen,” he said.
“You can’t reverse contamination, and the way sprouts are grown, if there is even the smallest amount of contamination present, it can multiply greatly and make people sick.”
A new study in fruit flies offers a broad view of the potent and sometimes devastating molecular events that occur throughout the body as a result of methamphetamine exposure.
The study, described in the journal PLoS ONE, tracks changes in the expression of genes and proteins in fruit flies (Drosophila melanogaster) exposed to meth.
Unlike most studies of meth, which focus on the brain, the new analysis looked at molecular changes throughout the body, said University of Illinois entomology professor Barry Pittendrigh, who led the research.
“One of the great things about working with fruit flies is that because they’re small, we can work with the whole organism and then look at the great diversity of tissues that are being impacted,” Pittendrigh said. “This is important because we know that methamphetamine influences cellular processes associated with aging, it affects spermatogenesis, and it impacts the heart. One could almost call meth a perfect storm toxin because it does so much damage to so many different tissues in the body.”
By tracking changes in gene expression and protein production of fruit flies exposed to meth, the researchers identified several molecular pathways significantly altered by the drug.
Many of these cascades of chemical reactions within cells are common to many organisms, including humans, and are similar even among very different families of organisms.
The researchers found that meth exposure influenced molecular pathways associated with energy generation, sugar metabolism, sperm cell formation, cell structure, hormones, skeletal muscle and cardiac muscles. The analysis also identified several new molecular players and unusual disruptions of normal cellular events that occur in response to meth, though the authors acknowledge that further work is required to validate the role of these pathways in response to meth.
Illinois crop sciences professor Manfredo Seufferheld, a co-author on the study, saw changes that indicate that meth exposure may alter the cell’s energy metabolism in a manner that mirrors changes that occur in rapidly growing cancer cells. Most types of cancer rely primarily on the rapid breakdown of glucose in a process called glycolysis, which does not require oxygen even when oxygen is available. In contrast, healthy cells tend to use oxidative respiration, a slower and more efficient energy-generating process that occurs in the presence of oxygen. This aberration in energy metabolism observed in cancer cells is called the Warburg effect.
“The discovery of the molecular underpinnings of the meth syndrome in Drosophila – based on a systems biology approach validated by mutant analysis – has the potential to be used in advancing our knowledge about malignant cell proliferation by understanding the connections behind the Warburg effect and cell death,” Seufferheld said.
Since glycolysis uses glucose to produce energy, the researchers tested the hypothesis that sugar metabolism is involved in the “toxic syndrome” spurred by meth. They found that meth-exposed fruit flies lived longer if they consumed trehalose, a major blood sugar in insects that also is an antioxidant.
Human meth users are known to crave sugary drinks, said lead author Lijie Sun. “And now we have evidence that increased sugar intake has a direct impact on reducing the toxicity of meth, at least in flies.”
The researchers found that meth caused changes that may interfere with the critical balance of calcium and iron in cells, and they were the first to identify numerous genes that appear to be involved in the meth-induced dysfunction of sperm formation.
“All in all, this study shows that Drosophila melanogaster is an excellent model organism in which to study the toxic effect of methamphetamine at the molecular level,” said Illinois postdoctoral researcher Kent Walters, an author on the study.
The study team also included researchers from the University of Nebraska (Jiri Adamec); Purdue University (William Muir, Eric Barker, Jun Xie, Venu Margam, Amber Jannasch, Naomi Diaz and Catherine Riley); Chung Hwa College of Medical Technology, Taiwan (Yueh-Feng Li); Carnegie Mellon University (Jing Wu); Indiana University (Jake Chen and Fan Zhang); and others at the
U. of I. (Hongmei Li and Weilin Sun). Lijie Sun, who earned her doctorate in Pittendrigh’s laboratory when he was a professor at Purdue, now is working at the J. Craig Venter Institute under Hamilton O. Smith, who won the 1978 Nobel Prize in the physiology or medicine category.
Source: University of Illinois at Urbana-Champaign
Atmospheric sciences professor Stephen Nesbitt, left, and graduate student Daniel Harnos analyzed passive microwave satellite data to identify telltale structural rings in tropical storms that are about to intensify into hurricanes.(Credit: Photo by L. Brian Stauffer)
Coastal residents and oil-rig workers may soon have longer warning when a storm headed in their direction is becoming a hurricane, thanks to a University of Illinois study demonstrating how to use existing satellites to monitor tropical storm dynamics and predict sudden surges in strength.
“It’s a really critical piece of information that’s really going to help society in coastal areas, not only in the U.S., but also globally,” said atmospheric sciences professor Stephen Nesbitt. Nesbitt and graduate student Daniel Harnos published their findings in the journal Geophysical Research Letters.
Meteorologists have seen large advances in forecasting technology to track the potential path of tropical storms and hurricanes, but they’ve had little success in predicting storm intensity. One of the biggest forecast problems facing the tropical meteorology community is determining rapid intensification, when storms suddenly transform into much stronger cyclones or hurricanes.
“Rapid intensification means a moderate-strength tropical storm, something that may affect a region but not have a severe impact, blowing up in less than 24 hours to a category 2 or 3 hurricane,” Harnos said. “This big, strong storm appears that wasn’t anticipated, and the effects are going to be very negative. If you don’t have the evacuations in place, people can’t prepare for something of the magnitude that’s going to come ashore.” For example, Hurricane Charlie, which hit southern Florida in 2004, was initially forecast as a category 1 storm. However, when it made landfall less than 24 hours later, it had strengthened to a category 4, causing major damage.
Rapid intensification is so hard to predict in part because it’s driven by internal processes within the storm system, rather than the better-predicted, large-scale winds that determine the direction of the storms. The satellite imagery most commonly used for meteorology only looks at the clouds at the top of the storms, giving little insight as to what’s going on inside the system.
Harnos and Nesbitt focused their study on passive microwave satellite imagery. Such satellites are used commonly for estimating precipitation, but the Illinois researchers focused on using these sensors to systematically observe hurricane structure and intensity changes. Their study was the first to use objective techniques to investigate a convective ring structure that has been observed in tropical cyclones.
“What makes it ideal for what we are doing is that it’s transparent to clouds. It senses the amount of ice within the clouds, which tells us the strength of convection or the overturn of the atmosphere within the hurricane,” Nesbitt said. “It’s somewhat like trying to diagnose somebody with a broken arm by taking a picture of the arm, versus being able to X-ray it.”
The researchers scoured data from passive microwave satellites from 1987 to 2008 to see how hurricanes behaved in the 24 hours before a storm underwent rapid intensification. Such a big-picture approach, in contrast to the case studies atmospheric scientists often perform, revealed clear patterns in storm dynamics. They found that, consistently, low-shear storm systems formed a symmetrical ring of thunderstorms around the center of the system about six hours before intensification began. As the system strengthened into a hurricane, the thunderstorms deepened and the ring became even more well-defined.
The study also looked at high-shear storms, a less common phenomenon involving atmospheric winds hanging with height. Such storms showed a different structure when intensifying: They form a large, bull’s-eye thunderstorm in the center of the system, rather than a ring around the center.
“Now we have an observational tool that uses existing data that can set off a red flag for forecasters, so that when they see this convective ring feature, there’s a high probability that a storm may undergo rapid intensification,” Nesbitt said. “This is really the first way that we can do this in real time rather than guessing with models or statistical predictions.”
Since passive microwave satellites orbit every three to six hours, meteorologists can use them to track tropical storms and watch for the telltale rings to give forecasters about a 30-hour window before a storm hits its maximum strength.
Next, the researchers hope to even further increase their forecasting ability by modeling the internal dynamics of the storm systems as they intensify to pinpoint the causes of the structural changes they observed and find out what drives the intensification process.
“The satellite gives up as snapshot of what’s taking place,” Harnos said. “We know what’s going on, but not how those changes are occurring to end up in the pattern that we’re seeing. So what we’re working on now is some computer modeling of hurricanes, both real storms and idealized storms, to see dynamically, structurally, what’s taking place and what changes are occurring to produce these patterns that we see in the satellite data.”
The NASA Hurricane Science Research Program supported this work.
Source: University of Illinois at Urbana-Champaign
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Not all strains of E.coli are harmful. However, the strain that has caused the German outbreak is very pathogenic. (Credit: Penn State)
Atmospheric sciences professor Stephen Nesbitt, left, and graduate student Daniel Harnos analyzed passive microwave satellite data to identify telltale structural rings in tropical storms that are about to intensify into hurricanes.(Credit: Photo by L. Brian Stauffer)