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Blocking Single Target May Prevent Lethal Aneurysms

Researchers have shown that removal of a single key protein can prevent early damage in blood vessels from triggering a later-stage, frequently lethal complication of atherosclerosis. By eliminating the gene for a signaling protein called cyclophilin A (CypA) from a strain of mice, the team was able to provide complete protection against abdominal aortic aneurysm (AAA). AAA leads to 15,000 deaths a year, mostly in aging men, when aneurysms rupture to spill blood into the abdomen, a fatal event in 90 percent of cases. When study mice were engineered to remove their CypA gene, none from that group developed AAA in the face of the hypertension and high cholesterol known to accelerate it. In contrast, 78 percent of mice with "normal" amounts of CypA developed AAA under the same conditions, 35 percent with a fatal rupture. The researchers also found high CypA levels in the rupture-prone vessels of humans with AAA, and that major drugs like statins reduce CypA levels, which may partly explain their benefit. “It is extremely unusual for the removal of one protein to provide absolute protection, but it makes perfect sense because cyclophilin A promotes three of the most destructive forces in blood vessels: oxidative stress, inflammation, and matrix degradation," said Dr. Bradford C. Berk, of the Aab Cardiovascular Research Institute at the University of Rochester Medical Center, and senior author of the study. "We are working to design anti-CypA drugs that will diminish the disease processes underlying AAA, atherosclerosis and hypertension." This study was published in the May 10 online edition of Nature Medicine. [Press release] [Nature Medicine abstract]

Alcohol Flushing Response May Indicate Cancer Risk

The alcohol flushing response, seen in approximately 36% of East Asians (Japanese, Chinese, and Koreans), may be an indictor of a much increased risk of esophageal cancer from alcohol consumption in these individuals, according to a recent article in PLoS Medicine. This is particularly unfortunate as esophageal cancer is one of the deadliest cancers worldwide, with five-year survival rates of 15.6% in the United States, 12.3% in Europe, and 31.6% in Japan, the authors noted. The flushing response is predominantly due to an inherited deficiency in the enzyme alcohol dehydrogenase 2 (ALDH2), and there is accumulating evidence that individuals deficient in ALDH2 are at a much higher risk of esophageal cancer than are those with normal levels of ALDH2. The authors advised that doctors should counsel their ALDH2-deficient patients to limit alcohol consumption and thereby reduce the risk of developing esophageal cancer. Clinicians can determine ALDH2 deficiency simply by asking about previous episodes of alcohol-induced flushing. As a result, ALDH2-deficient patients can then be counseled to reduce alcohol consumption, and high-risk patients can be assessed for endoscopic cancer screening. In view of the approximately 540 million ALDH2-deficient individuals in the world, many of whom now live in Western societies, even a small percent reduction in esophageal cancers due to a reduction in alcohol drinking would translate into a substantial number of lives saved, the authors asserted. [PLoS Medicine article]

Gecko’s Night Vision May Be Basis for Better Cameras, Contact Lenses

The key to the exceptional night vision of the nocturnal helmeted gecko is a series of distinct concentric zones of different refractive powers, according to a study published in the online Journal of Vision. Nocturnal geckos are among the very few living creatures able to see colors at night. "We were interested in the geckos because they, and other lizards, differ from most other vertebrates in having only cones in their retina," said project leader Dr. Lina Roth of Lund University in Sweden. "With the knowledge from the gecko eyes, we might be able to develop more effective cameras and maybe even useful multifocal contact lenses." The nocturnal gecko’s multifocal optical system is comprised of large cones, which the researchers calculated to be more than 350 times more sensitive than human cone vision at the human color vision threshold. The nocturnal gecko’s optical system gives them an advantage because light of different ranges of wavelengths can be focused simultaneously on the retina. Another possible advantage is that their eyes allow them to focus on objects at different distances. Therefore, the multifocal eye would generate a sharp image for at least two different depths. Geckos that are active during the day do not possess the distinct concentric zones and are considered monofocal, the researchers said. [Press release] [Journal of Vision abstract]

Source of Silkworm Attraction to Mulberry Leaves Discovered

Scientists have discovered the source of the silkworm’s attraction to mulberry leaves, their primary food source. A jasmine-scented chemical (cis-jasmone) emitted in small quantities by the leaves triggers a single, highly tuned olfactory receptor in the silkworms’ antennae, the researchers showed. The results are contrary to the prevailing belief that insects are generally attracted to their host plants through the recognition of a blend of volatile compounds by a combination of receptors, said Dr. Kazushige Touhara of The University of Tokyo, the senior author of the report. In addition to the new insights into insect olfaction, the findings may also have practical implications for those who raise silkworms for the production of silk, he added. The study was published online on May 7 in Current Biology. [Press release] [Current Biology abstract]

Sanfilippo Syndrome Might Be Treatable with Alzheimer Drugs

Scientists at UCLA have obtained evidence that a form of the rare genetic disease known as Sanfilippo syndrome may be treatable with new Alzheimer’s disease drugs directed against the P-tau protein. Four different enzyme deficiencies cause Sanfilippo syndrome, leading to the disorder's classification as type A, B, C, or D. The UCLA team studied type B, the second most common form, which causes severe mental retardation, dementia, and death as early as age 14. "We knew that Sanfilippo syndrome type B results from a mutation of the gene that produces the enzyme needed to break down sugar molecule chains [mucopolysaccharides] in the body," said Dr. Elizabeth Neufeld, of the David Geffen School of Medicine at UCLA, and senior author of the study. "We studied the disease in mice bred to possess the same gene defect seen in human patients." Neufeld's team found that mice with the defective gene produce higher amounts of two proteins called lysozyme and P-tau. They tracked the proteins to neurons in the medial entorhinal cortex, an important memory center in the brain. This is one of the first areas to be affected by Alzheimer's disease, and the region also has been implicated in abnormalities in Sanfilippo syndrome. Earlier research had linked high levels of lysozyme to the production of P-tau, a misshapen protein that helps form the strands that clump into tangles in the brain. These tangles impair neuron function and are a hallmark of Alzheimer's and other degenerative brain diseases. "This is really exciting," said Dr. Stanislav Karsten, also an author of the study. "If we can replicate our discovery of P-tau in the brains of human patients, it may be possible to treat Sanfilippo syndrome with new drugs created for Alzheimer's disease.

Marker in Surrounding Tissue Is Prognostic in Breast Cancer

Researchers have shown that a marker in tissue surrounding tumor cells is a new prognostic factor for patients with breast cancer. Absence of the market (caveolin-1) in stromal fibroblasts is associated with early disease recurrence, metastasis, and decreased patient survival. Stroma is non-cancerous connective tissue, which, in solid tumors, surrounds tumor cells. “The idea that a prognostic biomarker is present in the stroma rather than the epithelial cancer cell is paradigm-shifting," said Dr. Michael Lisanti, the senior of the study and editor-in-chief of the American Journal of Pathology. “Importantly, these findings could be developed into a diagnostic test that would not require DNA-based technologies. This inexpensive and cost-effective test would allow doctors to identify high-risk breast cancer patients at diagnosis and treat them more aggressively.” The absence of caveolin-1 in the stroma also appeared to be a marker for drug resistance in patients receiving the anti-cancer drug tamoxifen, the researchers said. “These are significant findings that do have to be validated in prospective breast cancer clinical trials,”said Dr. Richard Pestell, director of the Kimmel Cancer Center at Thomas Jefferson University, and an author of the study. “However, we should start taking the breast tumor stroma into our clinical considerations sooner, rather than later.” The study appears in the May 1 online edition of American Journal of Pathology, together with another group’s study on stromal expression of caveolin-1 in breast cancer. A related study was published online in Cancer Biology & Therapy.

Gold Nanorods May Permit Heat Treatment of Tumors

Scientists at MIT, together with collaborators, have developed gold nanorods that can home in on tumors and then, by absorbing energy from near-infrared light and emitting it as heat, destroy the tumors with minimal side effects. The light heats the nanorods, but passes harmlessly through tissue. Although it has long been known that heat can kill tumor cells, it has previously been difficult to heat the tumor cells specifically while leaving the surrounding tissue undamaged. In designing the nanorods, the researchers took advantage of the fact that blood vessels located near tumors have tiny pores just large enough for the nanorods to enter. The team developed a polymer coating for the particles that allows them to survive in the bloodstream longer than any other gold nanoparticles. In experiments in mice with tumors, the nanorods were injected into the bloodstream and accumulated in the tumors. With near-infrared laser treatment, the tumors disappeared in 15 days. The treated mice survived for three months with no evidence of recurrence, until the end of the study, while mice that received no treatment or only the nanorods or laser, did not. The researches noted that the gold nanorods also have potential in the detection and diagnosis of tumors, because the particles can be imaged by a technique known as Raman scattering. This work was reported in two recent papers, one in Cancer Research and the other in Advanced Materials. [MIT release]

Primordial Gene Might Permit Bypass of Mitochondrial Defects

Researchers have shown that by providing Parkinson-disease-model fruit flies with a gene they don’t normally possess, they can rescue the flies from their Parkinson-like symptoms, including movement defects and excess free radicals produced in mitochondria. The key gene (single-subunit alternative oxidase or AOX) essentially acts as a bypass for blockages in the so-called oxidative phosphorylation (OXPHOS) cytochrome chain in mitochondria. Dr. Howard Jacobs, who led the study at the University of Tampere in Finland, likens that chain to a series of waterfalls in a hydroelectric power station. Only, in the case of mitochondria, it is electrons that flow to release energy that is captured in molecular form. Defects in mitochondrial OXPHOS are associated with diverse and mostly intractable human disorders, the researchers said. Therefore, there's a chance that the strategy might also prove beneficial in mammals, including humans, which, like insects, have also lost the AOX gene over the course of evolution. On the other hand, most plants, animals, and fungi do possess an alternative mitochondrial respiratory chain, which can bypass the OXPHOS system under specific physiological conditions. Their findings led the researchers to conclude that “AOX appears to offer promise as a wide-spectrum therapeutic tool in OXPHOS disorders.” “OXPHOS dysfunction is not just a problem in some rare genetic disorders or in degenerative diseases,” Dr. Jacobs added. It's an issue in a very large number of pathologies—and a major cause of tissue damage after heart attack and stroke.

Next-Gen Sequencing Speeds Mutation Mapping in Fruit Flies

A novel whole-genome sequencing approach using Illumina next-generation sequencing technology has been developed and used for mapping single-base mutations in the fruit fly. The novel methodology promises to reduce the time and effort required to identify mutations of biological interest. “This approach will change the way fruit fly genetics is done,” said Scott Hawley, Ph.D., a co-equal senior author on the publication. “Traditional mapping approaches to identify mutations are inefficient procedures. Our whole-genome sequencing approach is fast and cost-effective. Among other potential uses, it also carries the potential to pinpoint inheritable molecular characteristics that are controlled by several genes at once.” Model organisms like fruit flies are used in research for studying both normal biological processes and human disease. Fruit fly genes can be inserted, deleted, or modified, and large numbers of flies can be randomly mutated to generate interesting phenotypes relevant to human disease. Finding the mutated gene responsible for an interesting phenotype is currently labor-intensive and time-consuming, and many mutations that cause medically relevant phenotypes are not discovered. The new approach lowers the barrier to finding mutations and may greatly accelerate the discovery of genes important for human health, the researchers suggest. The study was published in the May issue of Genetics. [Stowers Institute release] [Genetics abstract]

Study Supports Role of Autoimmunity in Narcolepsy

An immune system gene has been strongly associated with a form of narcolepsy, lending strength to the long-held belief that this sleep disorder is an autoimmune disease. The researchers suggest that this finding could have implications not just for narcolepsy, but for a wide range of autoimmune diseases. The gene is TCRA (T-cell receptor alpha), which codes for a receptor protein on T-cells. Narcolepsy is a disorder that causes disabling daytime sleepiness, irresistible bouts of sleep that can strike at any time, and disturbed sleep at night. This new study focused on a special form of the disease called narcolepsy with cataplexy, which is a sudden loss of muscle tone that can cause a person to collapse, with or without falling asleep. Approximately 1 in 2,000 people in the United States have narcolepsy-cataplexy. The symptoms of this disease have been shown to result from the death of a small group of brain cells that normally regulate the sleep-wake cycle by releasing hormone chemicals called hypocretins. Previous work had shown that almost everyone with narcolepsy-cataplexy has the same variant (HLA-DQB*0602) of a major histocompatibility gene. Because of HLA’s prominent role in immunity, it was hypothesized that narcolepsy-cataplexy might be caused by an autoimmune attack on the hypocretin-producing cells in the brain. The new study lends credence to this theory by implicating an immune system gene (TCRA).

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