Discovery of new target for breast cancer drugs

Main Category: Breast Cancer
Article Date: 24 Jul 2013 - 0:00 PDT
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Discovery of new target for breast cancer drugs

Scientists have identified higher levels of a receptor protein found on the surface of human breast tumour cells that may serve as a new drug target for the treatment of breast cancer. The results, which are published in EMBO Molecular Medicine, show that elevated levels of the protein Ret, which is short for "Rearranged during transfection", are associated with a lower likelihood of survival for breast cancer patients in the years following surgery to remove tumours and cancerous tissue.

"Our findings suggest that Ret kinase might be an attractive and novel alternative therapeutic target in selected groups of breast cancer patients," remarked Nancy Hynes, Professor at the Friedrich Miescher Institute for Biomedical Re-search and the University of Basel, Switzerland. "Initial experiments in mice that serve as model organisms for the study of breast cancer have revealed that specific inhibitors significantly block the spread of cancer and decrease the number of metastatic tumours found in the lungs."

The scientists examined tumour tissue microarrays of more than 100 breast cancer patients who had undergone surgery to remove their tumours. Antibodies were used to detect the levels of Ret in the samples. In other experiments, four different cancer cell lines were used and injected into mice to study the effects of Ret inhibitors on the progress and spread of the cancer.

"Our findings demonstrate that blocking Ret kinase not only decreases the growth of tumours but also impacts the potential of the cancer to spread throughout the body," Hynes said.

Targeting receptor tyrosine kinase enzymes with antibodies or small molecular inhibitors is a clinically validated approach for cancer therapy. However, only a subset of patients are eligible for these types of treatments which makes it essential to discover additional inhibitors that could be useful in breast cancer therapy.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our breast cancer section for the latest news on this subject.

Dr. Albana Gattelli was supported by grant KG101234 from Susan G. Komen for the Cure®

"Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells", Albana Gattelli, Ivan Nalvarte, Anne Boulay, Tim C. Roloff, Martin Schreiber, Neil Carragher, Kenneth K. Macleod, Michaela Schlederer, Susanne Lienhard, Lukas Kenner, Maria I. Torres-Arzayus and Nancy E. Hynes, doi: 10.1002/emmm.201302625

European Molecular Biology Organization

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Discovery of gene function may help prevent kidney stones

Main Category: Genetics
Also Included In: Urology / Nephrology
Article Date: 26 Jul 2013 - 2:00 PDT Current ratings for:
Discovery of gene function may help prevent kidney stones

The discovery of a gene's function in E. coli and other bacteria might lead to a probiotic to prevent the most common type of kidney stone, according to a Purdue University study.

Human cells can't metabolize oxalate, an acidic chemical found in nearly all plants we eat, so any oxalate we absorb from food must be excreted from the body. Calcium-oxalate urinary stones can form when oxalate reaches a high concentration in the kidneys. About 80 percent of kidney stones are composed of insoluble calcium oxalate.

T. Joseph Kappock, assistant professor of biochemistry, and his research team made the discovery during a study of genes in Acetobacter aceti, a harmless bacterium that is typically used to convert wine to vinegar. Acetobacter aceti, which normally lives on plant tissue, thrives in acidic conditions that easily kill most other bacteria, Kappock said.

The researchers were searching for other acids in addition to acetic acid, the acid present in vinegar, that the bacterium can metabolize.

"We were very excited when we realized E. coli has the same genetic setup as Acetobacter aceti," said Kappock, whose findings were published in the journal PLOS ONE.

Kappock and doctoral students Elwood A. Mullins and Kelly L. Sullivan found that Acetobacter aceti and E. coli each contain an enzyme with a previously unknown function, called YfdE in E. coli.

DNA sequencing had identified related genes in each bacterium, but provided little insight about its function.

"When we look at a bacterial genome by DNA sequencing, we can't tell what many of the proteins in the organism do," Kappock said. "I compare it to knowing that a vehicle has an internal combustion engine. You don't know if it's in an Indy car or a diesel truck. DNA sequencing tells us we have an internal combustion engine in this organism, but we don't know what it's for or what it can do."

Many other bacteria have the same genes but don't seem to be capable of using them.

"A few bacteria in the gastrointestinal tract eat oxalate, and we think we know how those work," Kappock said. "But we don't know why so many others are killed by oxalate, even though they have genes that would seem to be able to protect them. Oxalate is a very hard nut to crack. It's a very stable molecule that is difficult to decompose. The enzymes that process it are pretty specialized and don't seem to connect to normal bacterial metabolic pathways in an obvious way."

The researchers determined which chemicals are processed by the YfdE enzyme, following a hunch that it would use oxalate. Their results connected oxalate degradation to the core of bacterial metabolism.

Assigning a function to YfdE may help identify beneficial bacteria that could serve as probiotic agents in the human gastrointestinal tract to reduce the risk of kidney stone formation. Kidney stones, which affect more than 5 percent of the U.S. population, can cause painful blockages of the urinary tract.

"If we understand what bacteria need to degrade oxalate, then we might have a better idea how to identify strains that can do that, and thereby suppress the uptake of dietary oxalate" he said. "There are probably bacteria out there that have engineered themselves to do this for us."

Genome-sequencing information will increase the speed of the search, Kappock said.

"Because we've figured out what the gene product does, we will be able to find it in any organism and can zero in on those that might be beneficial," he said.

The researchers used X-ray crystallography to pinpoint the most important regions of the YfdE enzyme.

Kappock said the information has other applications, as well. Scientists and engineers who are interested in mapping and reprogramming microbial metabolism now know what one more gene product does.

"Our one piece of the puzzle will help others understand other metabolic networks," he said.

Agricultural Research at Purdue, the National Science Foundation and the U.S. Department of Energy funded the research.

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Abstract:

Acetyl-CoA:Oxalate CoA-transferase 1 Function and X-ray Crystal Structure of Escherichia coli YfdE

Elwood A. Mullins 1, 2; Kelly L. Sullivan 1; T. Joseph Kappock 1;

1 Dept. of Biochemistry, Purdue University, West Lafayette, Indiana, USA

2 Dept. of Chemistry, Washington University, St. Louis, Missouri, USA

Many food plants accumulate oxalate, which humans absorb but do not metabolize, leading to the formation of urinary stones. The commensal bacterium Oxalobacter formigenes consumes oxalate by converting it to oxalyl-CoA, which is decarboxylated by oxalyl-CoA decarboxylase (OXC). OXC and the class III CoA-transferase formyl-CoA:oxalate CoA-transferase (FCOCT) are widespread among bacteria, including many that have no apparent ability to degrade or to resist external oxalate. The EvgA acid response regulator activates transcription of the Escherichia coli yfdXWUVE operon encoding YfdW (FCOCT), YfdU (OXC), and YfdE, a class III CoA-transferase that is ~30% identical to YfdW. YfdW and YfdU are necessary and sufficient for oxalate-induced protection against a subsequent acid challenge; neither of the other genes has a known function. We report the purification, in vitro characterization, 2.1- A crystal structure, and functional assignment of YfdE. YfdE and UctC, an orthologue from the obligate aerobe Acetobacter aceti, perform the reversible conversion of acetyl-CoA and oxalate to oxalyl-CoA and acetate. The annotation of YfdE as acetyl-CoA:oxalate CoA-transferase (ACOCT) expands the scope of metabolic pathways linked to oxalate catabolism and the oxalate-induced acid tolerance response. FCOCT and ACOCT active sites contain distinctive, conserved active site loops (the glycine-rich loop and the GNxH loop, respectively) that appear to encode substrate specificity.

Purdue University

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Discovery reveals key mechanism responsible for herpes virus

Main Category: Infectious Diseases / Bacteria / Viruses
Article Date: 26 Jul 2013 - 1:00 PDT Current ratings for:
Discovery reveals key mechanism responsible for herpes virus

Herpes viruses are like tiny powder kegs waiting to explode. For more than 20 years scientists suspected that herpes viruses were packaged so full of genetic material that they built up an internal pressure so strong it could shoot viral DNA into a host cell during infection. No one had been able to prove that theory until now.

Carnegie Mellon University biophysicist Alex Evilevitch together with his graduate student David Bauer and University of Pittsburgh collaborators Fred Homa and Jamie Huffman have measured, for the first time, the pressure inside human herpes simplex virus 1 (HSV-1). The study, published online in the Journal of the American Chemical Society, provides the first experimental evidence of high internal pressure within a virus that infects humans. This phenomenon was previously only attributed to viruses that infect bacteria, called bacteriophages.

"Despite billions of years of evolution separating eukaryotic viruses and bacteriophages, the existence of an internal pressure capable of powering the ejection of DNA into a host cell has been conserved. This suggests that it is a key mechanism for viral infection across organisms and presents us with a new drug target for antiviral therapies," said Evilevitch, associate professor of physics.

Current antiviral medications are highly specialized. They target molecules essential to the replication cycle of specific viruses, so each medication is designed to treat only one type of viral infection. Additionally, since viruses mutate over time, they can become less susceptible to targeted medications. But designing drugs aimed at stopping a fundamental mechanism of viral infection, in this case the tightly packed genome that causes such high internal pressure, could yield new classes of broad-based, mutation-resistant antiviral treatments, according to Evilevitch.

Many viruses, whether they infect bacteria, plants or animals, are adept at packing long stretches of nucleic acid (DNA or RNA) within their nanometer-sized protein shells. HSV-1 contains double-stranded DNA that is 400 times longer than the radius of the viral shell it fills. The DNA gets packaged so tightly that it bends upon itself, resulting in repulsive forces that exert tremendous energy and pressure on the virus's outer shell. When HSV-1 infects a cell, it enters through the outer cell membrane and makes its way to the cell nucleus, where it docks in a small hole found in the nuclear membrane. That act is like a key opening a lock that allows the HSV-1 to eject its DNA into the cell nucleus.

For years scientists hypothesized that a high internal pressure inside eukaryotic viruses like HSV-1 enabled the virus to shoot its DNA into the host cell's nucleus. But it was impossible to measure HSV-1's internal pressure without knowing how to release the viral DNA in a controlled, experimental setting. Evilevitch's colleagues William Newcomb and Jay Brown, professors of microbiology and cancer biology at the University of Virginia's School of Medicine, discovered protein called UL6 that, when degraded, caused DNA to exit the virus. In his experiment, Evilevitch and Bauer degraded UL6, which triggered HSV-1 to eject its DNA. At the same time, they applied an external force to the virus and monitored how much DNA was released. When the external pressure reached tens of atmospheres, HSV-1 didn't release any DNA, indicating that the internal and external pressure were equal.

"This measurement of high internal pressure - tens of atmospheres - within a human virus is a fundamentally important discovery of the physical-chemical mechanism of eukaryotic viral infection," Evilevitch said.

The mechanism of pressurized infection found in HSV-1 is applicable to any of the eight known Herpes viruses that cause disease in humans, including Varicella zoster virus, which causes chickenpox in children and shingles in adults, and the Epstein-Barr virus, which causes mononucleosis and is associated with several types of cancer, such as Hodgkin's lymphoma.

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The study was funded by a National Science Foundation grant (CHE-1152770), the Swedish Research Council, a Public Health Service Grant (AI060836) from the National Institutes of Health and the Mellon College of ScienceDean's Fund.

Carnegie Mellon University

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Modern dentistry may benefit from discovery of an evolutionary compromise for long tooth preservation

Main Category: Dentistry
Article Date: 27 Jul 2013 - 0:00 PDT Current ratings for:
Modern dentistry may benefit from discovery of an evolutionary compromise for long tooth preservation

Researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and the Senckenberg Research Institute in Frankfurt am Main, Germany, have conducted stress analyses on gorilla teeth of differing wear stages. Their findings show that different features of the occlusal surface antagonize tensile stresses in the tooth to tooth contact during the chewing process. They further show that tooth wear with its loss of dental tissue and the reduction of the occlusal relief decreases tensile stresses in the tooth. The result, however, is that food processing becomes less effective. Thus, when the condition of the occlusal surface changes during an individual's lifetime due to tooth wear, the biomechanical requirements on the existing dental material change as well - an evolutionary compromise for longer tooth preservation.

First, the researchers created 3D digital models of three gorilla lower second molars differing in wear stages. In a second step they applied a Software tool (Occlusal Fingerprint Analyser) developed in the Senckenberg Research Institute to precisely determine tooth to tooth contacts. They then used an engineering approach, finite element analysis (FEA), to evaluate whether some dental traits usually found in hominin and extant great ape molars have important biomechanical implications.

The results show that in unworn and slightly worn molars (with a well-formed occlusal relief that is most effective for processing food) tensile stresses concentrate in the grooves of the occlusal surface. In such a condition, the different crests of a molar carry out important biomechanical functions, for example, by reinforcing the crown against stresses that occur during the chewing process. Due to a loss of tooth tissue and a reduction of the occlusal relief the functionality of these crests diminishes during an individual's lifetime. However, this reduced functionality of the crests in worn teeth is counterbalanced by an increase in contact areas during tooth to tooth contacts, which ultimately contributes to a dispersion of the forces that affect the occlusal surface.

This suggests that the wear process might have a crucial influence in the evolution and structural adaptation of molars enabling to endure bite forces and to reduce tooth failure throughout the lifetime of an individual. "It seems that we observe an evolutionary compromise for long tooth preservation. Even though worn teeth are not as efficient they still fulfill their task. This would not be the case if they were lost prematurely", says Stefano Benazzi of the Max Planck Institute for Evolutionary Anthropology. He adds: "Tooth evolution and dental biomechanics can only be understood, if we further investigate tooth function in respect to the dynamic changes of tooth structures during the lifespan of individuals".

"The results have strong implications for understanding the functional biomechanics of dental traits, for deciphering the evolutionary trend of our masticatory apparatus and might have important implications in modern dentistry for improving dental treatments", says Jean-Jacques Hublin, director of the Department of Human Evolution at the Max Planck Institute for Evolutionary Anthropology.

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Virus discovery: 'blast' mechanism used to infect host

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Main Category: Genetics
Article Date: 26 Jul 2013 - 1:00 PDT Current ratings for:
Virus discovery: 'blast' mechanism used to infect host

Researchers have discovered the first "pressure-driven infection mechanism" in a human virus, which blasts infectious DNA into cells with pressure eight times higher than that of a typical car tire.

The study, published in the Journal of the American Chemical Society, suggests that this discovery could open the door to new treatments for viral infections.

Researchers from the US and Sweden analyzed the pressure inside the herpes simplex virus 1 (HSV-1), the infection that causes cold sores.

It was found that the HSV-1 virus enters human cells, settles on the nucleus and then blasts its way into DNA using high pressure built up from a "nanometer-scale protein shell" called the capsid, researchers explain. The capsid is the shell that contains the viral genome.

The researchers say that the viruses responsible for infections such as influenza and HIV are quickly becoming resistant to drugs that target viral proteins. The proteins can quickly disguise themselves and become resistant to ant-viral drugs as a result of genetic mutation.

For example, previous research published in PLoS Computational Biology has suggested that drug resistance to HIV, the virus that causes AIDS, can be caused by pre-existing mutations, which can actually progress even more once treatment is initiated.

Findings such as this one have led to a search for weaknesses in viruses that do not involve viral proteins, the researchers add, a reason why this study was conducted.

Previous research has also shown many viruses that infect bacteria, called bacteriophages, use the same pressure-driven mechanism in order to blast their DNA into bacteria nuclei.

They add that the same mechanism also exists in eight related viruses, including chickenpox in children, shingles in adults, and the virus responsible for mononucleosis.

The researchers believe that evolution has meant that this technique is now apparent in viral infection, paving the way for the development of treatments that can defeat particular viruses, such as HSV-1, in the same way.

They say:

"Despite billions of years of evolution separating eukaryotic viruses and bacteriophages, pressure-driven DNA ejection has been conserved. This suggests it is a key mechanism for viral infection and thus presents a new target for antiviral therapies."

Written by Honor Whiteman

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Herpes Virus Genome, The Pressure Is On, published in The Journal of the American Chemical Society, July 5, 2013

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