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duminică, 5 august 2012

A Better Understanding Of Rhomboid Proteases May Lead To New Therapies For Malaria And Other Parasitic Diseases

Johns Hopkins scientists have decoded for the first time the "stability blueprint" of an enzyme that resides in a cell's membrane, mapping which parts of the enzyme are important for its shape and function. These studies, published in advance online in Structure and in Nature Chemical Biology, could eventually lead to the development of drugs to treat malaria and other parasitic diseases.

"[It's] the first time we really understand the architectural logic behind the structure of the enzyme," says Sinisa Urban, Ph.D., an associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine and an investigator at the Howard Hughes Medical Institute, who with his team has unlocked the mysteries of a special class of enzymes called rhomboid proteases.

Rhomboid proteases are present in many different organisms, and are a unique type of enzyme that resides in the cell's membrane where they cut proteins. Previously Urban and his colleagues demonstrated that the rhomboid enzyme is critical for Plasmodium falciparum, the parasite that causes malaria, to successfully invade red blood cells, a step that ultimately leads to infection. Urban says understanding the stability of rhomboid protease shape may impact the design of enzyme inhibitors - potential drugs. "These enzymes have no selective inhibitors," says Urban. "We really need to understand how [the enzyme] works - is it as stiff as a rock, or is it more gummy, like Jell-O?"

One challenge of studying rhomboid enzymes is that they are surrounded by membranes, making them more difficult to manipulate and work with. To address this, Urban's research team turned to a technique known as thermal light scattering, which heats enzyme samples to progressively higher temperatures while measuring the amount of light bouncing back off of the molecules. Enzymes that have broken from their normal shape will scatter light differently, and the temperature at which this occurs (in effect, the breaking point of the enzyme) indicates the inherent stability of the enzyme.

The researchers first precisely measured the stability of the rhomboid enzyme from E. coli bacteria. Surprisingly, says Urban, the rhomboid enzyme was more "Jell-O-like" than other membrane proteins with similar shapes. He guesses that this "jiggly shape" may help rhomboid proteases interact with other proteins that it cuts. To find which parts of the enzyme are most important for maintaining shape and which parts are more crucial for function, the researchers then made and tested 150 differently altered versions of the enzyme. They found four main regions important for maintaining shape and at least two regions important for function.

The researchers also took advantage of computer simulations to test their ideas about how the enzyme functions. Using a computer program model of the enzyme, they programmed in features of its natural membrane environment, which consists mostly of fats and is very limited in water. The computer program then simulated how this environment might influence the enzyme. Researchers found that the enzyme contains a special internal pocket for holding water molecules - a great advantage in its natural, water-limiting environment.

"We're very excited about our findings and are especially curious about the versions of the enzyme that lost function despite no obvious change in stability or shape," says Urban. Ultimately he hopes that a better understanding of rhomboid proteases will lead to new therapies for treating malaria and other parasitic diseases.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our tropical diseases section for the latest news on this subject. These studies were supported by the Howard Hughes Medical Institute, a National Institute of General Medical Sciences grant (GM079223), a National Institute of Allergy and Infectious Diseases grant (AI066025), the National Science Foundation (NSF) and the David and Lucile Packard Foundation.
Other researchers who participated in this study include Rosanna Baker, Yanzi Zhou, Syed Moin and Yingkai Zhang.
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luni, 12 decembrie 2011

PSA Testing, Combined With Other Relevant Patient Data Can Reduce Unnecessary Prostate Biopsies

Editor's Choice
Main Category: Prostate / Prostate Cancer
Also Included In: Preventive Medicine
Article Date: 12 Dec 2011 - 7:00 PST

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A study published online by the journal Cancer reveals that up to one-quarter of men could avoid biopsies and their associated risks with prostate cancer screening that combines an adjusted blood test with other factors including, the patient's family history, overall weight as well as the size of the gland.

According to the team led by Martin G. Sanda, MD, Director of the Prostate Center at Beth Israel Deaconess Medical Center and Professor of Urology at Harvard Medical School, other factors such as prostate size should be taken into consideration when determining which patient should have a biopsy, instead of using "one-size-fits-all" levels of PSA.

Other factors, such as prostate size, can significantly improve the ability of PSA testing to detect aggressive prostate cancers for which treatment is appropriate, while avoiding identification of indolent cancers that do not require treatment.

A second investigation published online in the journal Urologic Oncology, also led by Sanda, reveals that another way to determine if a biopsy is needed is testing for the presence of absence of genes commonly found in the urine of men in conjunction with a PSA test.

The novel suggested methods follow the United States Preventative Services Task Force expert panel conclusion that the present PSA-based prostate cancer screening causes harm through treatment or additional invasive testing, such as biopsies, and saves few or no lives.

Sanda explains:

"That's because prostate cancers can vary in aggressiveness and more men die of other causes aside from that cancer, and because the PSA test alone can not determine how dangerous any particular cancer may be. The US Preventative Services Task Force threw the baby out with the bathwater by their blanket recommendation against prostate cancer screening."

Sanda notes that, instead, PSA screening can be improved to identify only aggressive cancer for which treatment is indicated by adjusting PSA results for other considerations, such as size of prostate, obesity, and family history.

According to results from the multi-center study PSAD levels of less than 0.1 - in comparison to the unadjusted level of between 2.5 and 4 - can be a significant indicator of a potential cancer. Physicians determine the density by a using a digital rectal exam, allowing them to consider other factors like benign prostatic hyperplasia, an enlargement of the gland that affects all men as they age.

The researchers discovered that combining PSAD with the digital exam, an examination of the patient's family history and a body mass index of 25 or less, would avoid biopsy in around one-quarter of biopsy-eligible men.

The researchers state:

"Urological practice, patient outcome and cost-effectiveness of health care would each benefit from new targeted strategies, such as nomograms (a predictive tool) that improve prediction of aggressive cancers, to enable selective identification of candidate for prostate biopsy that would improve the yield of clinically significant, histologically aggressive cancers warranting subsequent definitive treatment."

In an additional multi-center investigation published in Urologic Oncology, investigators explain that a test taken after a digital rectal exam that looks for two specific genetic biomarkers (TMPRSS2:ERG and PCA3), could prevent biopsies in men whose PSA reading ranges between 2-10 and who poses both genes. This could potentially stop one-third of men undergoing unnecessary biopsies.

Sanda, explains:

"Urine testing for prostate cancer is
in its infancy".

Further research is currently underway thanks to a $3.1 million grant from the National Institutes of Health. The study is assessing novel blood and urine test for prostate cancer in over 2,400 men over the next 5 years with the aim of resolving over-diagnosis and over-treatment.

One of the main focuses of proposed study involves a community outreach effort led by BIDMC primary care physician J. Jacques Carter, MD, MPH, Medical Director of the Dana Farber Cancer Institute Prostate Cancer Screening and Education Program and an Assistant Professor of Medicine at Harvard Medical School. A vital component of this investigation will be African-American men, who seem to develop prostate cancer more prevalently, and who have a higher risk of dying from prostate cancer.

Written by: Petra Rattue

Visit our prostate / prostate cancer section for the latest news on this subject. Beth Israel Deaconess Medical Center Please use one of the following formats to cite this article in your essay, paper or report: