Underwater sponges and worms may hold key to cure for malaria

Sunday, 21 July 2013

Islamabad, July 22 (Newswire): Healing powers for one of the world's deadliest diseases may lie within sponges, sea worms and other underwater creatures.

University of Central Florida scientist Debopam Chakrabarti is analyzing more than 2,500 samples from marine organisms collected off deep sea near Florida's coast.

Some of them could hold the key to developing drugs to fight malaria, a mosquito-borne illness that kills more than 1 million people worldwide annually. Chakrabarti is pursuing this study with Amy Wright of Harbor Branch Oceanographic Institute, Fort Pierce, whose team has collected these samples from a depth up to 3000 feet.

Chakrabarti is excited about the early promising results -- preliminary tests identified about 300 samples that can kill malaria parasites. He's also concerned, however, that the Gulf of Mexico oil spill may wipe out species that could hold healing properties for many deadly diseases.

"There is a very good possibility that the answers to cancers, malaria and other diseases may be found in the ocean," he said. "Why am I so optimistic? Just consider that the oceans cover 70 percent of the planet. Among 36 of the phyla of life, 34 are found in marine environment whereas the land represents only 17 phyla, and we haven't even begun to explore the oceans' depths.

"But I'm worried. Who knows what we may be losing."

He watches the news while continuing his research in hopes of finding answers to malaria, a disease he's dedicated his life to combating. There is no FDA-approved vaccine for malaria, and people are becoming more resistant to the drugs available to treat it.

Chakrabarti and Wright landed a $500,000 grant from the National Institutes of Health and National Institute of Allergy and Infectious Diseases for their study.

So far, Chakrabarti and his two graduate students have conducted preliminary testing of more than 2,500 samples from the Harbor Branch collection. They conducted tests to evaluate growth inhibitory properties of these samples for malaria parasite growing inside human red blood cells in culture.

One active sample derived from a marine sponge contained the compound Nortopsentin. Because of this compound's initial promise, Chakrabarti said, he's already filed an application for patent protection.

Harbor Branch is one of only three organizations in the country that has the capability to collect deep-sea samples. It has submersible vehicles that dive 3,000 feet underwater to collect samples off Florida's coast. Wright directs the biomedical-marine research program at Harbor Branch.

Chakrabarti's approach of identifying new drugs from marine sources builds on prior research around the globe.

In May, the American Society of Clinical Oncology announced results from a Japanese study concluding that the drug eribulin, derived from sea sponges, was effective in helping patients fight breast, colon and urinary cancer. Scientists in Australia are diving into the Great Barrier Reef to explore the potential healing powers of marine creatures living there.

Locally, Gregory Roth, director of medical chemistry and exploratory pharmacology at the Sanford-Burnham Medical Research Institute is working with Harbor Branch on similar research. Sanford-Burnham is one of the UCF College of Medicine's partners at its new health sciences campus in Lake Nona.

Chakrabarti will continue analyzing samples, particularly the 300 already identified as promising, during the next year.

"If we can find two or three good molecules that can be easily synthesized in a lab and that can prevent malaria, I'd be very happy," he said.

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Discovery suggests possible treatment strategy for aggressive leukemias

Islamabad, July 22 (Newswire): Researchers at Duke University Medical Center have identified a mechanism that could explain how patients move into the worst phase of chronic myelogenous leukemia (CML).

Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML.

This same molecular pathway may also be related to other aggressive leukemias, as well as solid tumors like glioblastoma (a severe form of brain cancer) and breast cancer.

With collaborators at other institutions, the Duke team looked at 120 human specimens from patients representing different phases of CML progression. They found that Musashi levels increased dramatically as the disease became more aggressive.

"We found high levels of Musashi in all of the human advanced phase CML samples we studied," said senior author Tannishtha Reya, Ph.D., an associate professor of pharmacology and cancer biology at Duke.

"The fact that this pattern was seen in all of the human cells, regardless of patients' gender or ethnicity, and in people on three continents, marked it as potentially a major signal that needed to be studied in as much depth as possible," Reya said.

The work appears in Nature online on July 18.

Because CML progression is marked by a block in cell maturation (called differentiation) and an increase in immature cells, the team wanted to learn whether this was driven by an aberrant reversal of the signals that regulate cell differentiation. They focused on Numb, a molecule that is known to control differentiation during normal development.

The team used mice to compare the chronic (less harmful) and blast-crisis (most harmful and severe) phases of CML. They found much lower levels of Numb in the blast-crisis phase mice.

"It is not always clear if a pathway that appears to be important in mouse models will be relevant in human disease," Reya said. "In this case, however, the data and patterns are so strong in human patient samples that pursuing these findings becomes critical."

This led them to explore the way that Numb was being repressed in advanced disease, and whether this repression contributes to the maintenance of blast-crisis phase. They focused on the RNA-binding protein Musashi, which had previously been shown to repress Numb in other systems.

The Musashi protein was named for a Samurai warrior who fought with two swords, because the loss of Musashi in fruit flies (where the gene was discovered) resulted in a developmental defect in which flies had double bristles, reminiscent of Musashi's swords.

Reya's team found that Musashi is particularly elevated in stem cells and needed for their growth, which could help explain why it is co-opted to promote the growth of immature cells in cancers as well. Musashi expression was 10 times higher in the more immature blast crisis CML phase. It may be a target for future therapies because blocking Mushashi could block cancer growth, Reya said.

"Our current work shows that activating Numb, or blocking Musashi can inhibit blast-crisis CML," Reya said.

Reya explained that there are two basic approaches to fighting cancer cell growth. One is to trigger programmed cell death in cancer cells or to block their growth directly. The other method, which may work in cases where the cancer is composed of immature cells, is to force these cells to mature and differentiate.

"The resulting depletion of immature cells can deliver a heavy blow to the continued growth of the cancer, as is seen in this study," Reya said.

Since high levels of Musashi appear to be an early marker of advanced CML, this might be a tool to determine patient prognosis as well, Reya said.

She said reports of higher levels of Musashi in glioblastoma and lower levels of Numb in high-grade breast cancer raise the possibility that the Musashi-Numb pathway could also be involved in solid cancers.

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New genomics-based approach to understand origin of cancer subgroups

Islamabad, July 22 (Newswire): Scientists have long recognized that cancers may look the same under the microscope, but carry different mutations, respond differently to treatment and result in vastly different outcomes for patients.

Now St. Jude researchers have developed a new approach that uses genomic information from different species to understand the biology that drives the formation of these different cancer subtypes.

The approach was developed by studying a tumor called ependymoma that affects the brains and spines of children and adults, but may also translate to other forms of cancer.

The research demonstrates for the first time that ependymomas in different regions of the nervous system arise when subtypes of stem cells found there acquire specific mutations.

The research also led to discovery of the first gene, called EPHB2, proven to cause ependymoma and has created the first accurate laboratory model of this disease.

The research was published in the advance online publication of the scientific journal Nature and is authored by Richard Gilbertson, M.D., Ph.D., a member of the St. Jude Departments of Developmental Neurobiology and Oncology.

"The approach we have developed provides a flexible way for scientists around the world to test the hypothesis that subsets of different cancers arise when particular mutations occur in particular cell types," Gilbertson said. "Because the laboratory models developed from this approach accurately model patient subgroups, they can then be used to develop and tailor effective new treatments for these patients."

The project builds on earlier work from Gilbertson's laboratory into the role that normal stem cells play in cancer.

The body relies on stem cells, which can divide and take on more specialized functions, to keep organs repaired and operating smoothly. The research included scientists from seven institutions in the U.S., Canada and Great Britain.

For this study, investigators gathered 204 ependymomas from patients in the US, Canada and Europe to conduct the most comprehensive analysis yet of the ependymoma genome. Researchers found the pattern of DNA gain or loss differed depending on the ependymoma's location in the brain or spine and uncovered nine subtypes of the disease.

The analysis also identified more than 200 genes as potentially important for triggering the tumor or helping the cancer spread. The list included EPHB2, a gene that regulates stem cell division and was recently linked to intestinal tumors. In this study, investigators linked EPHB2 to just one ependymoma subtype.

Researchers also tracked the different stem cell populations that give rise to ependymomas. Using an algorithm developed by Stanley Pounds, Ph.D., associate member in the St. Jude Department of Biostatistics, researchers compared patterns of gene expression in human ependymomas with gene expression in stem cells from different regions of the nervous systems of both embryonic and adult mice.

The mathematical tool made it possible for the first time to compare global gene expression patterns between species.

The exercise linked one subtype of the human cancer with a particular subpopulation of mouse nervous system or neural stem cells.

The stem cells also lacked the tumor suppressor genes Ink4a/Arf. When extra copies of EPHB2 were added to those neural stem cells and the cells were implanted in the forebrains of mice, half the mice developed brain tumors within 200 days.

Scientists went on to show the tumors were identical to human ependymomas by several different measures. In contrast, no ependymomas developed when extra copies of EPHB2 were inserted into other subpopulations of mouse neural stem cells.

Additional testing found that the mouse ependymoma model matched just one subtype of human ependymomas but no other form of common human brain tumors.

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Kabul Postcard: Newly paved sidewalks, a lion on the roof

Tuesday, 16 July 2013

Kabul, July 17 (Newswire): I've just returned to Kabul after a month out of the country. In a place where it sometimes feels like nothing changes, a lot has changed.

First, a few oddities. An Afghan businessman on my street apparently bought a lion cub and has been keeping it on his roof. I'm not sure if that has anything to do with the fact that I have yet to see any of the ubiquitous, dust-caked street dogs in the neighborhood since I returned, but I don't miss them.

Also, the average daytime temperature is 15 to 20 degrees higher that it was a month ago, which unfortunately brings out the pungent aroma from the open sewer trenches that line Kabul's streets.

The currency, the Afghani, has continued its downward slide in value, and the Internet here certainly hasn't gotten any faster.

A lot of foreigners left while I was away – journalists, aid workers, diplomats. While some will be replaced, some won't - at least not on a permanent basis - as organizations continue to downsize here as does the U.S. military forces, which will end its combat mission next year.

One of the most positive changes is that our street is finally paved. When I left in May, it was getting close, but every time it was close before, the workers would dig cavernous new trenches to repair water lines or sewer leaks. It seemed a Sisyphean process.

It seems construction in general has been hopping for the last month. On the drive in from the airport, I saw a number of buildings that were either much taller than when I left, or seemingly complete.

Here, construction projects are often cloaked with a green mesh - kind of a nylon burlap that looks tacky at best. Once buildings reach a certain phase of construction, the shroud comes down, and suddenly there is a shining new building.

And, that's the case a block from our house. At one end of the street is a gleaming new office building. At the other end, what had been a derelict looking wall has been torn down, and now there is a giant new wedding hall that was in full swing last night.

In a city where most buildings are old and drab, wedding halls are some of the most modern and flashy looking buildings in Kabul.

And, across the city, derelict buildings are coming down and new ones are rising from the ashes. It's really a shocking amount of change in a month.

Really, it's a continuum of change that I can see since my first visit to the city in 2009. There are countless new office and apartment buildings, more shops, more houses climbing up the craggy peaks across the city, and there are vastly more people. There was barely any traffic on the rough roads back in 2009, and not nearly the crush of vendors and pedestrians along the streets.

On one level, it seems like a healthy sign of growth, , it's also a case of a city growing much faster than the infrastructure and services.

Not everything was positive during my absence. The Taliban has carried out three high-profile attacks in the past month. In one, a suicide bomber detonated his vehicle outside the Supreme Court and killed 17 civilians.

In a pre-dawn raid, militants attacked the military section of Kabul Airport, and shut down the facility for several hours.

, militants managed to get inside the first layer of security around the presidential palace and kill three guards in the attack.

Our driver says that everyone he's talked to in the last month thinks things are getting worse. They are increasingly concerned about security as international forces draw down, and they'd happily trade paved roads for better security.

Though, for the last year I've been living in Kabul, just about everyone you talk to feels that the city is becoming less safe. So, every time you hear something rumble outside, you hope it's a backhoe and not a bomb.

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