Scientists have identified a key gene in the pathogenesis of inflammatory breast cancer (IBC), which is the most lethal form of primary breast cancer, often striking women in the prime of life and causing death within 18 to 24 months. The disease-related gene is eIF4GI, a translation initiation factor. Researchers found that this gene is overexpressed in the majority of IBC patients and enables the formation of small, highly mobile clusters of cells (tumor emboli) that are responsible for the rapid metastasis that makes IBC such an effective killer. “The tragedy of IBC is that it is often misdiagnosed and misclassified,” said Dr. Robert Schneider, senior author of the report. “Rather than presenting as a “typical” lump, IBC looks like an inflammation of the breast and is frequently mistaken for an infection. Physicians often prescribe antibiotics, losing valuable time for treating this fast-moving killer.” He noted that while IBC accounts for just several percent of all breast cancer cases, it takes a disproportionately high toll in mortality and has an incidence that is 50 percent higher in African American women. He added that there has been little progress in treating IBC over the past two decades, and there are no drugs specifically for this form of cancer. The new findings on eIF4GI could lead to the identification of new approaches, therapies, and a new class of drugs to target and treat IBC. This would be a critical development in the fight against IBC, which responds poorly to chemotherapy, radiation, or any other current treatments for breast cancer, Dr. Schneider noted. This research, conducted by scientists at New York University and George Washington University, was reported online in Nature Cell Biology on June 14.
Researchers at Johns Hopkins and the University of Texas-Houston have shown that a gene, located in a chromosome 4 region statistically associated with gout, is functionally associated with the disease. The gene is ABCG2 (ATP-binding cassette, subfamily G, 2) and the researchers showed that it is a previously unidentified urate efflux transporter. The researchers further showed that the native ABCG2 protein is located in the brush border membrane of proximal kidney tubule cells where it mediates renal urate secretion. Introduction of a common SNP mutation into the gene resulted in 53% reduced urate transport rates in an experimental model. Data from a population-based study supports the fact that this particular SNP is a causal variant in the gout-associated region on chromosome 4. The authors also said that their data indicates that this common casual variant is responsible for at least 10 percent of all gout cases in whites. Noting that gout affects approximately 3 million people in the United States and that present treatments are often insufficient, the researchers suggested that ABCG2 represents an attractive drug target. This work was published online on June 8 in PNAS. Gout is a disease hallmarked by elevated levels of uric acid in the bloodstream. In this condition, crystals of monosodium urate, a uric acid salt, are deposited on the articular cartilage of joints, tendons, and surrounding tissues. The disease is marked by transient painful attacks of acute arthritis initiated by crystallization of urates within and about the joints, and can eventually lead to chronic gouty arthritis and the deposition of masses of urates in joints and other sites. [PNAS abstract]
In a remote region of the Russian Caucasus Mountains, a previously unknown and entirely unique form of plant root has been discovered. The root belongs to the small alpine plant Corydalis conorhiza and, unlike normal roots that grow into the soil, these roots extend upward, against gravity, through layers of snow. Given this novel behavior, the scientists have termed them “snow roots.” “This is a completely new discovery,” said Dr. Johannes Cornelissen, the senior author of the study. “Snow roots are thus far unknown and a spectacular evolutionary phenomenon.” The team made its discovery high up in the Caucasus Mountains, where the ground remains covered in snow for much of the year. As the snow melted at the height of summer, the scientists noted that C. conorhiza plants were surrounded by a network of above-ground roots, stretching uphill and to each side for around 50 cm. During the spring and perhaps also winter, these roots extend into the surrounding snow and during the summer they die and decompose, which may explain how they had remained undiscovered. C. conorhiza also possesses normal roots which anchor the plant to the ground and take up nutrients such as phosphorus and nitrogen. Cornelissen’s team hypothesized that the additional snow roots allow C. conorhiza to take nitrogen directly from the snow. Many mountain plants take up nitrogen from melted snow soaking into the ground only after snow melt. However, an impenetrable ice crust prevents C. conorhiza from doing this, and therefore the plant is forced to depend upon the snow roots. Further study confirmed that the snow roots are anatomically very different from normal soil roots, and that they are specifically adapted for the fast uptake and transport of nitrogen. This work was published online on June 4 in Ecology Letters.
By administering a specific miRNA molecule that is reduced in hepatocellular carcinoma (HCC), scientists have halted the progression of liver tumors in mice. The results demonstrate for the first time that therapeutic delivery of a miRNA in an animal can result in tumor suppression, without the need for specifically targeting the cancer-causing oncogene. “This concept of replacing microRNAs that are expressed in high levels in normal tissues, but lost in diseases hasn’t been explored before,” said Dr. Joshua Mendell, senior author of the study. “Our work raises the possibility of a more general therapeutic approach that is based on restoring microRNAs to diseased tissues.” HCC, which is the third leading cause of cancer deaths, expresses a reduced number of miRNAs, including miR-26a. By combining miRNA technology developed at Johns Hopkins, with the gene delivery expertise at Nationwide Children’s Hospital, the reporting researchers were able to successfully deliver a recombinant adeno-associated virus (AAV) carrying miR-26a in a mouse model of HCC. This gene therapy strategy inhibited growth of cancer cells and led to tumor reduction and cell death, without causing toxic side effects to the remainder of the liver. The research team was made up of collaborators from Johns Hopkins, Nationwide Children’s Hospital, and Ohio State University. This work was published in the June 12 issue of Cell. [Press release 1] [Press release 2] [Cell abstract]
In a mouse system, UCLA researchers have identified an enzyme (Idol) that orchestrates the breakdown of LDL receptors and results in higher levels of LDL (“bad cholesterol”) in the blood stream. By blocking Idol’s activity, the researchers triggered cells to make more LDL receptors and to remove more LDL from the body. Statin drugs also reduce LDL levels by boosting cells’ production of the LDL receptor. The current findings could lead to a new drug that works in conjunction with statins, or that could be taken by patients who cannot tolerate statins’ side effects. “We only know of three pathways that regulate the LDL receptor. The first two are already targeted by existing drugs,” explained Dr. Peter Tontonoz, senior author of the report. “Idol is the first mechanism discovered in several years that may lead to a new medication designed to control cholesterol levels.” The work was published in the June 11 online edition of Science. [Press release] [Science abstract]
According to a Purdue University study, the introduction of a new hybrid of the all-but-extinct American chestnut tree might bring back the tree and serve to reduce the amount of carbon in the atmosphere and slow global climate change. Dr. Douglass Jacobs, the lead author of the report, found that American chestnuts grow much faster and larger than other hardwood species, allowing these trees to sequester more carbon than other trees over the same period. And because American chestnut trees are more often used for high-quality hardwood products such as furniture, they hold the carbon longer than does wood used for paper or other low-grade materials. Carbon dioxide is considered a major greenhouse gas, responsible for rising global temperatures. Dr. Jacobs said that trees absorb about one-sixth of the carbon emitted globally each year. Increasing the amount that can be absorbed annually could make a considerable difference in slowing climate change, he said. At the beginning of the last century, the chestnut blight, caused by a fungus, rapidly spread throughout the American chestnut’s natural range, which extended from southern New England and New York, southwest to Alabama. About 50 years ago, the species was nearly gone. New efforts to hybridize remaining American chestnuts with blight-resistant Chinese chestnuts have resulted in a species that is about 94 percent American chestnut with the protection found in the Chinese species. Dr. Jacobs said that these new trees could be ready to plant in the next decade, either in existing forests or former agricultural fields that are being returned to forested land. This work was published in the June issue of Forest Ecology and Management.
Using powerful “next-generation” sequencing technology, researchers in Canada have sequenced the entire genome of a rare and often untreatable form of ovarian cancer (granulosa cell tumors) from four individuals and shown that the tumors share a single base change in the gene FOXL2. This gene encodes a transcription factor known to be critical for granulosa cell development. The research team further validated its work by examining a large number of additional tumor samples from across Canada and around the world, and the team is satisfied it has been able to validate that this mutation is present in almost all granulosa cell tumors and not in unrelated cancers. Most types of cancers, including most ovarian cancers, have a broad range of genetic abnormalities. The current finding shows that granulosa cell tumors have a characteristic single DNA spelling mistake that can serve as an easy-to-read identity tag for this cancer type. “This is really a two-fold discovery,” said Dr. David Hunstman, senior author of the research report. “It clearly shows the power of the new generation of DNA sequencing technologies to impact clinical medicine, and for those of us in the area of ovarian cancer research and care, by identifying the singular mutation that causes granulosa cell tumours, we can now more easily identify them and develop news ways to treat them.” For this effort, the research team used next-generation sequencing machines that are able to decode billions of nucleotides at rapid speed, together with new computer techniques to quickly assemble the data. “This task would have been unfathomable in terms of both cost and complexity even two years ago,” said Dr. Marco Marra, also an author of the report. This work was published in the June 11 issue of the New England Journal of Medicine.
Researchers at the M.D. Anderson Cancer Center have identified four related new potential targets for breast cancer therapies. These potential targets are three lysophosphatidic acid (LPA) receptors (LPA1, LPA2, and LPA3) and the LPA-producing enzyme, autotoxin (ATX). “Lysophosphatidic acid is the single most potent known cellular survival factor,” said senior author Dr. Gordon Mills. It binds to a series of G protein-coupled receptors to spark normal cell proliferation, viability, production of growth factors, and survival. The current research shows that this powerful network is hijacked to initiate breast cancer and fuel tumor growth, invasion, and metastasis. The authors show that breast cancer-resistant mice, when engineered to overexpress any one of the four molecules, develop invasive and metastatic mammary cancers. “We’ve compiled lots of evidence that they (LPA1, LPA2, LPA3, and ATX) are associated with cancer; what’s been missing is proof that they could cause cancer. There are no questions left; they should be targeted.” A number of drugs that target the receptors and ATX are currently in preclinical development, Dr. Mills said. “Now we have transgenic mouse models to test drugs to go forward against these targets.” The current research was published in the June edition of Cancer Cell. [Press release] [Cancer Cell abstract]
The brilliant white shell of an obscure beetle (Cyphochilus) has provided scientists with insights as to how to produce a brighter coating for white paper. The novel coating would also be thinner and lighter than current coatings and this would translate into reduced transportation costs, while simultaneously reducing the economic and environmental costs of manufacture. Cyphochilus is native to south-east Asia, and it is believed that its whiteness evolved to mimic local white fungi as a form of camouflage. In 2007, research conducted at the University of Exeter and Imerys Minerals Ltd., and published in Science, revealed how the beetle produces its brilliant whiteness using a unique surface structure of long, flat, ultrathin scales with highly random internal 3-D structures–ideal for creating whiteness, which results from the scattering of all colors simultaneously. In the new work, members of the same research team showed how some of the beetle’s shell structure can be mimicked to produce thinner, whiter coatings for white paper. “It is interesting to consider that clues found in a small, obscure beetle could find application in large-scale industry,” one of the researchers noted. “Taking this concept forward is an interesting challenge, but we have good ideas about our next steps and, if successful, feel that such developments might have profound implications for future commercial white coatings.” The current research was published in the June 10 issue of Applied Optics. [Press release] [Applied Optics abstract]
Scientists at MIT and collaborating institutions have shown that a naturally occurring, non-toxic glucose derivative, GLD, can be used to compromise the immunity of termites and make them more vulnerable to lethal microbial infections. Insect pests such as termites cause damage to crops and man-made structures estimated at over $30 billion per year, imposing a global challenge on the human economy, the authors noted. They said that the use of GLD may lead to the development of non-toxic, sustainable pest control methods. Termites normally secrete a form of an antimicrobial protein into their nests to prevent pathogenic infections. The authors reported a technique to block this protein’s effects with GDL. They found that adding GDL to termite nests caused the termites to die more quickly at the hands of fungi that normally infect termites, as well as at the hands of opportunistic bacteria. The authors suggested that GDL, which is also biodegradable, and other similar molecules could be developed for food processing and storage and for use in building materials to protect against insect attacks. Plants could be engineered to produce GDL at high amounts in specific locations to increase their immunity, the authors suggested. This work was published online on June 8 in PNAS. [PNAS abstract]