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Archive - Feb 2010

Date

February 19th

Many Copy Number Variations Universal Among Diverse Tumors

An international team of researchers has created a genome-scale map of 26 different cancers, revealing more than 100 genomic sites where DNA from tumors is either missing or abnormally duplicated compared to normal tissues. The study, the largest of its kind, finds that most of these genetic abnormalities are not unique to one form of cancer, but are shared across multiple cancers. "Our findings show that many genome alterations are universal across different cancers. Although this has been known for some types of changes, the degree to which so many alterations are shared was pretty surprising to us," said senior author Dr. Matthew Meyerson, a professor of pathology at the Dana-Farber Cancer Institute and senior associate member of the Broad Institute of Harvard and MIT. "It suggests that, in the future, a driving force behind cancer treatment will be common genomic alterations, rather than tumors' tissue of origin." In 2004, a scientific team led by researchers at the Dana-Farber Cancer Institute and the Broad Institute launched a project to systematically map genetic changes across different cancers. They focused on a particular type of DNA change in which segments of a tumor's genome are present in abnormal numbers of copies. Instead of the usual two copies, tumors often carry several copies of one piece of DNA (an "amplification") or may lack it altogether (a "deletion"). These genetic abnormalities are known as somatic copy-number alterations or SCNAs. As the foundation for their analysis, the scientists collected over 2,500 cancer specimens representing more than two dozen cancer types, including lung, prostate, breast, ovarian, colon, esophageal, liver, brain, and blood cancers.

Study Distinguishes Between “Driver” and “Passenger” Cancer Mutations

A new study of mutations in cancer genomes suggests how researchers can begin to distinguish the “driver” mutations that push cells towards cancer from the “passenger” mutations that are by-products of cancer cell development. The study also shows that at least one in nine genes, on average, can be removed from human cancer cells without killing the cells. This is in sharp contrast to the corresponding figure for genes in normal human cells [X chromosome (1 in 100 genes); normal human genome (1 in 50 genes)]. Thus, cancer cells seem to be more tolerant to gene loss than the cells of healthy people and can lose a much greater proportion of their genes without losing the ability to live and grow. Many cancer genomes are riddled with mutations. The vast majority of these are likely to be passengers—i.e., mutations that don't contribute to the development of cancer, but have occurred during the growth of the cancer--while a small minority are the critical drivers of cancer growth and proliferation. The challenge of efficiently picking out the guilty drivers in the huge set of mutations found in a cancer genome has yet to be fully met. "It is essential that we can distinguish the drivers from the passengers because knowing the driver mutations, and hence the critical genes they are in, leads to understanding of the cellular processes that have been subverted in cancers, and hence to new drugs," explained the Wellcome Trust Sanger Institute’s Dr. Michael Stratton, senior author of the report. "Our study provides one example of how researchers can sift through the large numbers of a particular type of mutation present in cancer genomes in order to distinguish drivers from passengers."

February 18th

Additional Drug Reduces Lesions in Relapsing Multiple Sclerosis

An international team of researchers has found that adding a humanized monoclonal antibody called daclizumab to standard treatment reduces the number of new or enlarged brain lesions in patients with relapsing multiple sclerosis (MS). Daclizumab is specific for CD25, a protein that is expressed on activated T cells, and binding of daclizumab to CD25 results in selective inhibition of these activated T cells. Daclizumab treatment has been studied in patients with human autoimmune conditions, such as MS, that are characterized by abnormal T-cell responses. "Previous research has shown that treatment with daclizumab reduced multiple sclerosis disease activity," said Dr. John W. Rose, professor of neurology at the University of Utah School of Medicine, and senior author on the current article. "Our work in the CHOICE trial [a Phase 2, randomized, double-blinded, placebo-controlled clinical study] shows that daclizumab significantly reduces MS lesion formation in people with active relapsing disease." In addition to finding that add-on treatment with high-dose daclizumab resulted in a significantly lower number of new or enlarged MS lesions, the researchers found that patients treated with either high- or low-dose daclizumab had a seven to eight times higher number of immune cells called CD56bright natural killer cells (NK cells). Previous research has shown that untreated MS patients have lower numbers of these NK cells than healthy individuals. "Several lines of evidence point to a potential function for CD56bright natural killer cells in regulating the immune system," explained Dr. Rose.

Genome-Based Blood Tests May Usher in Personalized Medicine for Cancer

Data from the whole-genome sequencing of tumors from individual cancer patients may be used to develop individualized blood tests that can help physicians tailor treatments to the individual patient, according to results reported by researchers from Johns Hopkins and Life Technologies. The genome-based blood tests, believed to be the first of their kind, may be used to monitor tumor levels after therapy and determine cancer recurrence. This ground-breaking work may help bring the age of personalized medicine right to the cancer patient’s bedside. The sequencing in this project was carried out using the SOLiD next-generation sequencing platform (photo) from Life Technologies."We believe this is the first application of newer generations of whole-genome sequencing that could be clinically useful for cancer patients," says Dr. Victor Velculescu, co-director of the cancer biology program at Johns Hopkins and senior author of the report. "Using this approach, we can develop biomarkers for potentially any cancer patient." In their study, the scientists scanned the genomes of patients' tumors looking for alterations that they say most researchers have not been looking for—i.e., rearrangements of large chunks of DNA rather than changes in a single DNA letter among billions of others. Such DNA rearrangements are widely known to occur exclusively in cancer cells, not normal ones, making them ideal biomarkers for cancer. The researchers call their new approach Personalized Analysis of Rearranged Ends (PARE). "PARE uses genetic characteristics unique to the tumor to monitor disease progression. By exploiting rearrangements specific to the patient's tumor, we have developed a personalized approach for detection of residual disease," said lead author Rebecca Leary, a graduate student at the Johns Hopkins Kimmel Cancer Center.

February 17th

Mystery of King Tut’s Death Possibly Solved

A combination of bone disease and malaria infection likely contributed to the early death of Egypt’s King Tutankhamun, according to researchers who used a combination of anthropological, radiological, and DNA-based genetic studies to analyze the king’s mummy. The scientists also putatively identified other members of Tutankhamun’s immediate lineage, including his father, mother, and a grandmother. The 18th dynasty (circa 1550-1295 B.C.) of the New Kingdom (mid-16th to early 11th century B.C.) was one of the most powerful royal houses of ancient Egypt, and included the reign of Tutankhamun, probably the most famous of all pharaohs, although his tenure was brief. He died in the ninth year of his reign, circa 1324 B.C., at age 19 years. "Little was known of Tutankhamun and his ancestry prior to Howard Carter's discovery of his intact tomb (KV62) in the Valley of the Kings in 1922, but his mummy and the priceless treasures buried with him, along with other important archeological discoveries of the 20th century, have provided significant information about the boy pharaoh's life and family," the researchers wrote. With regard to their current research, the scientists noted that "several pathologies, including Kohler disease II (bone disorder), were diagnosed in Tutankhamun; none alone would have caused death. Genetic testing for STEVOR, AMA1, or MSP1 genes specific for Plasmodium falciparum (the malaria parasite) revealed indications of malaria tropica in four mummies, including Tutankhamun's. These results suggest avascular bone necrosis (condition in which the poor blood supply to the bone leads to weakening or destruction of an area of bone), in conjunction with the malarial infection as the most likely cause of death in Tutankhamun.

New Pathway Plays Role in Organ Tissue Repair and Regeneration

Scientists have discovered a molecular pathway that works through the immune system to apparently reestablish a developmental program that is beneficial for the repair and regeneration of damaged kidney tissues. This discovery may lead to new therapies for repairing injury in the kidney, and perhaps in a number of other organ systems as well. Acute kidney injury is a significant cause of kidney disease, cardiovascular complications, and early death, affecting as many as 16 million children and adults in the United States. There are currently no effective treatments for acute kidney injury--a growing problem in hospitals and clinics, according to the study's co-senior authors, Dr. Richard Lang, from Cincinnati Children's Hospital Medical Center, and Dr. Jeremy Duffield, from Brigham and Women's Hospital of Harvard Medical School. The newly discovered molecular repair pathway involves white blood cells called macrophages--part of the immune system--that respond to tissue injury by producing a protein called Wnt7b. The research team identified the macrophage-Wnt7b pathway during experiments in mice with induced kidney injury. Wnt7b is already known to be important to the formation of kidney tissues during embryonic organ development. In this study, the scientists found that the protein helped initiate tissue repair and regeneration in injured kidneys. “Our findings suggest that by migrating to the injured kidney and producing Wnt7b, macrophages are re-establishing an early molecular program for organ development that also is beneficial to tissue repair," said Dr. Lang. "This study also indicates the pathway may be important to tissue regeneration and repair in other organs." This research was conducted by an international team from eight research institutions and was reported online on February 16, 2010 in PNAS.

Crickets Warn Unborn Offspring of Spider Danger

New research shows that crickets, which abandon their eggs before they hatch, can warn their unborn offspring about potential predator threats, such as spiders. Scientists placed pregnant crickets into enclosures containing a wolf spider. The spiders' fangs were covered with wax so that the spiders could stalk the crickets, but couldn't kill them. After the crickets laid their eggs, the researchers then compared the behavior of those offspring to offspring whose mothers hadn't been exposed to spiders. The differences were significant. When placed into a terrarium with a hungry wolf spider, the crickets born of spider-exposed mothers were more likely to seek shelter and stay there. They stayed hidden 113 percent longer—and as a result had higher survival rates—than offspring from mothers that hadn't been exposed to spiders. Another experiment showed that the "forewarned" crickets were more likely to freeze when they encountered spider silk or feces—a behavior that could prevent them from being detected by a nearby spider. The results suggest that "the transfer of information from mother to offspring about predation risk, in the absence of any parental care, may be more common than one might think," said Dr. Jonathan Storm, a co-author of the study. This research was carried out by Dr. Storm, now of the University of South Carolina-Spartanburg, and Dr. Steven Lima of Indiana State University. The study was published in the March 2010 issue of American Naturalist. [Press release] [American Naturalist abstract]

February 16th

Odorants May Have Potential in Early Detection of Lung Cancer

Small-molecule volatile organic compounds (odorants) in urine may be useful in diagnosing lung cancer at an early stage, according to results of a mouse study by scientists at the Monell Chemical Senses Center, the Panasonic Corporation, and the University of Pennsylvania. These molecules, which can be perceived as odors (especially by animals), have been shown to function as “signatures” that convey social, emotional, and health information to other members of the species. The results of other studies support the hypothesis that odorants can be detected in the breath of lung cancer patients by smell (dogs were trained to do this, for example) or through bioanalytical techniques such as solid-phase microextraction followed by gas chromatography. Analysis of breath samples, however, is cumbersome and technically challenging, thus limiting its applicability. Lung cancer is the leading cause of cancer-related deaths throughout much of the world, and the only treatment with a high rate of cure is surgical resection of early disease (before metastatic spread occurs). Because only about 25 percent of cases are diagnosed at this early stage, effective early diagnostic techniques are urgently needed. In the current study, the scientists demonstrated that mice can be trained to discriminate between urinary odors of mice with and without experimental lung tumors, demonstrating that odorants are sufficient to identify tumor-bearing mice. Consistent with this result, chemical analyses of urinary odorants demonstrated that the amounts of several compounds were dramatically different between tumor and control mice. These chemical analyses were carried out using solid-phase microextraction followed by gas chromatography combined with mass spectrometry.

February 15th

Scientists Discover Switch That Turns On Metastasis

A specific protein called disabled-2 (Dab2) switches on the process that releases cancer cells from the original tumor and allows the cells to spread and develop into new tumors in other parts of the body, according to a report by scientists from the Cleveland Clinic, Case Western Reserve University, and collaborating institutions. The process called epithelial-mesenchymal transdifferentiation (EMT) has been known to play a role in releasing cells (epithelial cells) on the surface of a solid tumor and transforming them into transient mesenchymal cells, i.e., cells with the ability to migrate and start to grow a new tumor. This is often the fatal process in breast, ovarian, pancreatic, and colorectal cancers. The researchers knew that transforming growth factor beta (TGF-beta) induces EMT, but they did not know how. In their research, they found that TGF-beta triggers the formation of the Dab2 protein and that it is the Dab2 protein that activates the EMT process. Among the group’s findings was that if Dab2 was knocked out in animal models, EMT did not occur. "If we can understand the signaling pathway for modulating EMT, then we can design drugs to delay or halt EMT cells and control tumor progression," said Dr. Gi Jin, one of the authors of the report. This work was published online on February 14, 2010 in Nature Cell Biology. [Press release] [Nature Cell Biology abstract]

Bacteria-Killing Proteins Address Immune Blind Spot to Blood Type Antigens

A set of proteins found in the human intestine can recognize and kill bacteria that have human blood group antigens on their surfaces, according to collaborating scientists from the Emory University School of Medicine in the United States and the University of Sao Paulo in Brazil. "It's like having a platoon in an army whose sole purpose is to track down enemy soldiers that are wearing the home country's uniforms,” said Emory’s Dr. Richard Cummings, senior author of the report. The potential problem is that the human body’s adaptive immunity system, as a self-protective mechanism, eliminates any of its immune cells that recognize the body’s own blood group antigen type (A, AB, or B). That means that the adaptive immune system is potentially vulnerable to attack by bacteria that express a human blood group antigen on their surfaces. The scientists investigated how humans cope with this potentially dangerous vulnerability. Emory graduate students Connie Arthur and Dr. Sean Sowell identified two particular intestinal proteins (galectin-4 and galectin-8) that kill strains of E. coli that express human blood group antigens on their surfaces. The proteins do not kill E. coli strains that do not express these antigens on their surfaces. The researches further found that the killing activity of both galectin-4 and galectin-8 is mediated by their C-terminal domains, occurs rapidly, takes place independently of complement, and is accompanied by disruption of membrane integrity. "These proteins are separate from antibodies and other parts of the immune system," Dr. Cummings said. "They kill bacteria like E. coli O86 all by themselves within a couple of minutes." The E. coli O86 strain has molecules on its surface like those in humans with blood type B.