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Purdue takes prostate cancer treatment from concept to clinical trial

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.

 

Source: Purdue University

Published on 7th July 2011

Deadly E. coli outbreak in Germany should be a warning, expert says

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.”
Source: Pennsylvania State University
Published on 21st June 2011

Fruit flies on meth: Study explores whole-body effects of toxic drug

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

Published June 2nd 2011

Ring around the hurricanes: Satellites can predict storm intensity

 

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

Published May 21st 2011

Even in Winter, Life Persists in Arctic Seas

Photo of the USCGC Healy breaking through the Bering Sea waves.


(USCGC Healy breaking through the Bering Sea waves. Credit: Chantelle Rose/NSF)

 

Despite brutal cold and lingering darkness, life in the frigid waters off Alaska does not grind to a halt in the winter as scientists previously suspected. According to preliminary results from a National Science Foundation- (NSF) funded research cruise, microscopic creatures at the base of the Arctic food chain are not dormant as expected.

 

After working aboard the U.S. Coast Guard icebreaker Healy for six weeks in waters where winds sometimes topped 70 knots, wind chills fell to -40 degrees and samples often had to be hustled safely inside before seawater froze to the deck, researchers are back in their labs, assembling for the first time a somewhat unexpected picture of how microscopic creatures survive winter in the Bering, Chukchi and Beaufort seas.

 

Although they have much more work to do before publishing their results, they say they are surprised on a number of fronts, including the discovery of active zooplankton–microscopic organisms that drift or wander in ocean, seas or bodies of fresh water.

 

“The zooplankton community seemed to be quite active, said Carin Ashjian of the Woods Hole Oceanographic Institution, the chief scientist on the expedition. “They were feeding at low rates. That was a surprise.”

 

Ashjian is scheduled to discuss the preliminary results from the cruise during a session at the American Geophysical Union’s 2012 Ocean Sciences Meeting in Salt Lake City, Utah this week.

 

Although perhaps arcane to non-scientists, the kinds of information gathered by the researchers previously was unattainable and is vital if scientists are to understand how a changing climate in the Arctic might affect the food chain, which extends upward from zooplankton through marine mammals to, eventually, subsistence hunters.

 

The ecological balance–and potential changes in that balance–of the northern waters potentially has large repercussions for commercial fisheries. The Bering Sea, for example, supports one of the world’s most productive fisheries.

 

“This kind of research is really improving our fundamental understanding of this very important part of the ocean and giving us new information that we can put to use both in numerical models that are used to investigate ecosystem responses to environmental changes, but also in scientists’ conceptual models of how these ecosystems really function,” Ashjian said.

 

But, Ashjian noted, as the researchers, including scientists from the University of Rhode Island and the University of Alaska Fairbanks, were working in an area of the globe that is poorly understood by scientists even in the warmest months of the year and seldom visited in winter, discovery was one object of the expedition.

 

“Our understanding of biological and physical processes during the winter in the Arctic is severely limited because it is so difficult to access these winter seas,” Ashjian said. “In particular, understanding of the overwintering strategies of one of the dominant copepod species in the region is not well understood.”

 

Copepods are crustaceans that form a link in the food web between the primary-producing phytoplankton and the plankton-feeding fish as well as being important prey for large baleen whales–such as the bowhead–in the Arctic.

 

In spite of the challenges associated with working in severe weather and in the sea ice, the cruise was highly successful. In the Chuckchi Sea more sampling stations than originally planned were occupied, even though sea ice was forming as the cruise progressed and almost all of the stations in the Chukchi Sea were occupied in ice cover. Ocean-water temperatures were near the freezing point of seawater at all depths, with little to no stratification of the water column on the shallower shelves.

 

Despite the ice cover and very short days, low levels of phytoplankton–photo-synthesizing microscopic organisms–were still detected.

 

“This was a remarkably productive cruise, especially given the conditions under which these scientists were working,” said William Wiseman, Natural Sciences Program Manager in the Office of Polar Programs’ Division of Arctic Sciences at NSF. “It is easy to forget that, even in the early part of the 21st century, much of the globe remains unexplored by science. As a result, cruises like this are able to produce fundamental and vital knowledge about complex ecological systems; which is why NSF supports exactly this kind of research at the intellectual and physical frontiers.”

 

Technology aboard the Healy also allowed the ship to do what earlier Polar explorers–and even Ashjian’s colleagues a few years ago–could not; share their experience with students ashore.

 

Chantelle Rose, who teaches at Graham High School in St. Paris, Ohio, joined the cruise as part of the NSF-funded PolarTREC (Teacher and Researchers Collaborating and Exploring) program.

 

She posted on-line journals from the ship and communicated remotely with students, activities that are both in keeping with NSF’s goal of combining research and education.

 

“I know that we need to engage the younger generation in science, but working scientists generally are not great teachers,” Ashjian said. “Whenever I always go into a classroom, I worry that I am not always effective. That’s a big concern for me. So I like this partnership: I think that this is a good way to get science out into the classroom.”

 

What they continue to learn from specimens and data gathered on the cruise, which wrapped up in January may well change scientific conceptions of how animals at the bottom of the Arctic food chain persist through the Arctic winter and help scientists to improve models designed to predict the effects of a changing climate.

 

 

Source: National Science Foundation

A Biodiversity Discovery That Was Waiting in the Wings–Wasp Wings, That Is

Photo showing wing size differences between two Nasonia wasp species.


Wing size differences between two Nasonia wasp species are the result of newly discovered genetic differences between the species. The diversity of size and shape differences between other animal species may have similar origins. Credit: David Loehlin, University of Wisconsin, Madison


From spaghetti-like sea anemones to blobby jellyfish to filigreed oak trees, each species in nature is characterized by a unique size and shape. But the evolutionary changes that produce the seemingly limitless diversity of shapes and sizes of organisms on Earth largely remains a mystery. Nevertheless, a better understanding of how cells grow and enable organisms to assume their characteristic sizes and shapes could shed light on diseases that involve cell growth, including cancer and diabetes.

 

Providing new information about the evolution of the diversity of sizes and shapes in nature is a study identifying genetic differences between two closely related species of Nasonia wasps. These differences give males of one of the Nasonia species small flightless wings and the males of the other Nasonia species flight-worthy wings that are twice as large.

 

Jack Werren and David Loehlin at the University of Rochester led the research. (Loehlin is now a post-doc at the University of Wisconsin-Madison). Funded by the National Science Foundation (NSF), this week’s issue of Science covers the research.

 

The research team identified the chromosomal location of the gene responsible for wing size in each of the two Nasonia species, the differences between the DNA sequences of these genes, as well as regulatory controls that determine when, where and how long each species’ growth gene is turned on.

 

These genetic differences alter both the locations of growth centers in the wings and the timing of growth during Nasonia development–factors that give each species its distinct wing size. As evidence that the identified genes control wing size, the researchers nearly doubled the wing size of the small-winged species by cross-breeding into it the gene from the big-winged species.

 

Interestingly, Loehlin says the team’s results indicate multiple genetic changes caused the differences in Nasonia wing size-changes, and these changes may have occurred incrementally. “It is possible that the diversity of size and shape differences between other animal species have similar origins in regulator DNA. And the gene we identified is thought to control growth in many other animals, including people.”

 

The researchers suspect that the small winged Nasonia species evolved from the big-winged species, but it is also possible that the two species evolved in the opposite order.

 

“Understanding the types of changes in DNA that are responsible for evolution is critical to unraveling the causes of life’s diversity,” says Samuel Scheiner, a program director at NSF. “The recent explosion of new tools for DNA sequencing is now allowing this understanding. This study demonstrates that changes in gene regulation can be important for such evolution.”

 

The two studied species of Nasonia wasps were chosen for this research because their close genetic relationship coupled with the large difference in their wing sizes makes genetic comparisons between them particularly easy. Nasonia wasps have become a model system for studying evolution because their genetics and breeding system simplify the identification of genetic changes behind complex traits.

 

 

Source: National Science Foundation

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