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Scientists Identify Gene for Lung Cancer in Never-Smokers

Variations in a gene called GPC5 have been identified which might contribute to a significantly higher risk of developing lung cancer in people who have never smoked. The findings, from genome-wide association studies to outline the genetic changes involved in lung cancer in never smokers, suggest that GPC5 might be a new target for investigation and drug development, and could be used to identify high-risk individuals. Lung cancer in people who have never smoked (defined as those who have smoked fewer than 100 cigarettes in their lifetimes) is an increasing public-health problem, responsible for 25 percent of all lung cancer cases worldwide. Despite attempts to identify the specific genetic mechanisms responsible, the causes of lung cancer in never-smokers have remained poorly understood. Recent studies have identified several candidate genes that have a moderate effect on the risk of lung cancer, but no study has identified the genetic basis of lung cancer in never smokers. "This is the first gene that has been found that is specifically associated with lung cancer in people who have never smoked," said the study's senior author, Mayo Clinic genetic epidemiologist Dr. Ping Yang. "What's more, our findings suggest GPC5 may be a critical gene in lung cancer development and genetic variations of this gene may significantly contribute to increased risk of lung cancer," she said. "This is very exciting. Findings from this study concern pure lung cancer that is not caused by smoking, and it gives us some wonderful new avenues to explore. Our suspicion all along is that this is a distinct disease, and that is why we undertook this study," Dr. Yang said.

New Ways to Kill Tuberculos Organism Discovered

Two novel ways to kill the bacterium (Mycobacterium tuberculosis) that causes tuberculoisis (TB) have been discovered by researchers at the Albert Einstein College of Medicine, together with collaborators. TB still kills an estimated 2 million people each year and the scientists believe that their findings could lead to a potent TB therapy and would also prevent resistant TB strains from developing. "This approach is totally different from the way any other anti-TB drug works," said Dr. William R. Jacobs, Jr., the study's senior author and professor of microbiology & immunology and of genetics at Einstein. "In the past few years, extremely drug-resistant strains of TB have arisen that can't be eliminated by any drugs, so new strategies for attacking TB are urgently needed." In searching for a new Achilles' heel for M. tuberculosis, Dr. Jacobs and colleagues focused on an enzyme called GlgE. Previous research had suggested that GlgE might be essential for the growth of TB bacteria. GlgE would also be an excellent drug target because there are no enzymes similar to it in humans or in the bacteria of the human gut. The GlgE research revealed a previously unknown enzymatic pathway by which TB bacteria convert the sugar trehalose (consisting of two glucose molecules) into longer sugar molecules known as alpha glucans, building blocks that are essential for maintaining bacterial structure and for making new microbes through cell division. GlgE was the third of four enzymes involved in this pathway leading to alpha glucans molecules. Sure enough, when the researchers inhibited GlgE, the bacteria underwent "suicidal self-poisoning"--a sugar called maltose 1-phosphate accumulated to toxic levels that damaged bacterial DNA, causing the death of TB bacteria grown in Petri dishes as well as in infected mice.

Nanoparticles Deliver Effective siRNAs to Tumor Cells

A California Institute of Technology (Caltech)-led team of researchers and clinicians has published the first proof that a targeted nanoparticle—used as an experimental therapeutic and injected directly into a patient's bloodstream—can traffic into tumors, deliver double-stranded small interfering RNAs (siRNAs), and turn off an important cancer gene using a mechanism known as RNA interference (RNAi). Moreover, the team provided the first demonstration that this new type of therapy, infused into the bloodstream, can make its way to human tumors in a dose-dependent fashion—i.e., a higher number of nanoparticles sent into the body leads to a higher number of nanoparticles in the tumor cells. These results demonstrate the feasibility of using both nanoparticles and RNAi-based therapeutics in patients, and open the door for future "game-changing" therapeutics that attack cancer and other diseases at the genetic level, said lead author Dr. Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech. The scientific results are from an ongoing phase 1 clinical trial of these nanoparticles (image, Caltech/Derek Bartlett) that began treating patients in May 2008. Phase 1 trials are, by definition, safety trials; the idea is to see if and at what level the drug or other therapy turns harmful or toxic. These trials can also provide an in-human scientific proof of concept—which is exactly what is being reported in the current article. The current results were published online on March 21, 2010 in Nature. [Press release] [Nature abstract]

Study of Rare Genetic Disorder Suggests Role for Fibrillin-1 in Scleroderma

By studying the genetics of an autosomal dominant disorder called “stiff skin syndrome,” a rare congenital form of scleroderma, researchers at the Johns Hopkins University School of Medicine and collaborating institutions have learned more about the much more common acquired form of scleroderma, also called systemic sclerosis. Systemic sclerosis affects approximately one in 5,000 people and leads to hardening of the skin, as well as to other debilitating and often life-threatening problems. “[Acquired] scleroderma is a common and often devastating condition, yet its cause remains mysterious. My greatest hope is that this work will facilitate the development of new and better treatments,” said senior author Dr. Harry C Dietz, the Victor A. McKusick Professor of Genetics and Director of the Johns Hopkins William S. Smilow Center for Marfan Syndrome Research. Acquired scleroderma generally affects previously healthy young adults, causing scarring of skin and internal organs that can lead to heart and lung failure. “Most often individuals with [acquired] scleroderma do not have other affected family members, precluding use of genetic techniques to map the underlying genes. Instead, we turned to a rare but inherited form of isolated skin fibrosis called “stiff skin syndrome,” hoping to gain a foothold regarding cellular mechanisms that might prove relevant to both conditions,” said Dr. Dietz. A number of clues led Dr. Dietz and his team to strongly suspect a role for the connective tissue protein fibrillin-1 in these skin conditions. First, excess collagen is a hallmark feature of both stiff skin syndrome and acquired scleroderma.

Differences in Transcription Factor Binding May Explain Many Human Differences

Differences in gene expression associated with differences in transcription factor binding may help explain many of the differences among individual humans, according to a team of Yale University researchers and collaborators. Transcription factors bind to DNA regions and set in motion programs of increased or decreased gene expression through their influence on the binding of RNA polymerase and the transcription of DNA to RNA. Using the technique of chromatin immunoprecipitation followed by sequencing (ChIP-Seq), the authors showed, on a genome wide basis, that the binding regions for RNA polymerase II and NF-kappa B differed by 25 percent and 7.5 percent, respectively, between any two human individuals in samples of lymphoblastoid cells from 10 individuals of various ancestries. RNA polymerase II, which is active in all cells, transcribes DNA into RNA, and its activity is dependent on the appropriate transcription factors being present at the DNA binding regions. NF-kappa B is a transcription factor that is activated by stress, plays a key role in immune responses to infections, and has been implicated in several diseases, including cancer. Approximately 19,000 and 15,500 binding regions were found for RNA polymerase II and NF-kappa B, respectively, in the study. The researchers found that differences in the binding of RNA polymerase II and NF-kappa B at DNA regions were frequently associated with SNPs and genomic structural variants (SVs), such as duplications, deletions, and inversions of long stretches of DNA, and were often correlated with differences in gene expression, suggesting functional consequences of binding variation.

Cough Medicine Ingredient Shows Promise for Prostate Cancer Treatment

Researchers have shown that, in mice, the cough medicine ingredient noscapine inhibits prostate tumor growth and also limits the spread of tumors without causing any side-effects. Noscapine, a non-addictive derivative of opium, has been used worldwide since the 1950s as an ingredient in over-the-counter cough medicines and was originally suggested as an anti-cancer agent in the early 1960s--but major studies of its anti-cancer properties have only taken place in recent years. The current research focused on pre-treating mice with noscapine before injecting them with prostate cancer cells. This resulted in the tumor growth rate being two-thirds lower in the noscapine group than in a non-noscapine group. The study also found that metastasis rates to the lung were 80 percent lower in the mice pre-treated with noscapine. The scientists further noted that the noscapine group suffered no cancer-related weight loss--compared with significant weight loss in the non-noscapine group. They concluded that noscapine administered as a preventive measure may offer significant benefits in the management of prostate cancer, a disease that kills more than 28,000 men in the U.S. each year. The research team is now hoping to further its efforts by examining the effects of noscapine as a prophylactic agent given to patients following prostate cancer surgery or radiation. "Based on our research so far, we believe that noscapine could be a very promising treatment to prevent recurrence in such cases due to its excellent safety record and oral bioavailability," said co-author Dr. Israel Barker, Founder and Medical Director of the Prostate Cancer Research and Education Foundation. This new pre-clinical research was reported in Volume 30(2) of Anticancer Research.

Most Domesticated Dogs Originated in Middle East, Study Suggests

Most domesticated dogs likely originated from gray wolves in the Middle East, with only some possibly originating in Europe or Asia, according to a new genetic analysis by an international team of scientists led by UCLA biologists. The team reported genetic data from 912 dogs from 85 breeds (including all the major ones) and 225 wild gray wolves (the ancestor of domesticated dogs) worldwide, including populations from North America, Europe, the Middle East and East Asia. The scientists used molecular genetic techniques to analyze more than 48,000 genetic markers (SNPs) on a genome-wide basis in the dogs and wolves. The team has not yet pinpointed a specific location of origin in the Middle East. The new research results were published online on March 17, 2010 in Nature. In their work, the researchers found evidence for certain candidate genes that might have been important in the early domestication of dogs. There was evidence of positive selection for two SNPs located near genes associated with memory formation and/or behavioral sensitization in mouse or human studies. There was also evidence of positive selection for a third SNP that is located near the dog counterpart of the gene associated with Williams-Beuren syndrome in humans. This syndrome is characterized by social traits such as exceptional gregariousness. The current results were consistent with earlier analyses suggesting that three groups of ancient breeds (origins >500 years ago) are distinct from modern domestic dogs that are the products of the controlled breeding practices of the Victorian era (circa 1830-1900). These ancient breeds consist of an Asian group (dingo, New Guinea singing dog, chow chow, Akita, and Chinese Shar Pei), a Middle Eastern group (Afghan hound and saluki), and a northern group (Alaskan malamute and Siberian husky).

Molecular Basis of Detecting Noxious Chemicals Has Ancient Origin

Chemical nociception, the detection of painful, tissue-damaging chemicals like those found in wasabi, tear gas, and cigarette smoke, is triggered, in humans, by a protein receptor known as TRPA1, which is found in the nose, mouth, skin, lungs, and GI tract. Studying the chemical sensors of fruit flies, researchers at Brandeis University have discovered that flies use their ortholog of the human TRPA1 sensor for the same purpose. Using a combination of behavioral, physiological, and phylogenetic analyses, the scientists found evidence suggesting that this defensive response to noxious compounds has been present across an immense evolutionary time scale and links humans, insects, and many other organisms back to a common ancestor that lived approximately 500 million years ago, said senior author and biologist Dr. Paul Garrity. The ability to detect such noxious compounds, known as reactive electrophiles—a class of compounds that humans find pungent and irritating--is important for animal survival, prompting them to avoid potentially toxic food or dangerous situations. These receptors give animals an advantage in survival by acting as a biological warning system, as it were. In humans, chemical nociception can cause pain and inflammation. "What the study, spearheaded by Kyeongjin Kang in my lab, shows, is that this chemical sense is nearly as ancient as vision," said Dr. Garrity. "While many aspects of other chemical senses, like taste and smell, have been independently invented multiple times over the course of animal evolution, the chemical sense that detects these reactive compounds is different.

Dietary Tryptophan Reduces Aggression in Pigs

Feeding the amino acid tryptophan to young female pigs as part of their regular diet makes them less aggressive and easier to manage, according to a study by Agricultural Research Service (ARS) scientists and collaborators at Purdue University. The tryptophan-enhanced diet reduced aggression and overall behavioral activity among young female pigs during the eight-month study. Tryptophan, which is only acquired through diet, is the precursor for the calming cerebral neurotransmitter serotonin. Keeping swine calm is important, because aggressive behavior can harm them and increase feed and medical costs for producers. The supplemented diet resulted in calmer animals, mainly at the younger age. Persistent aggression in pigs can cause chronic stress, leading to poorer welfare, increased disease susceptibility, and reduced growth and efficiency. To test aggression, researchers put an "intruder" pig in the pen until an aggressive interaction was triggered or for a maximum of five minutes. Pigs receiving the high-tryptophan diet showed less aggression--fewer attacked the intruder, and those that did attack were slower to do so--compared with the animals that didn't get the supplement. Pigs form social groups that, over time, develop into stable hierarchies or "pecking orders." However, when new individuals are introduced, aggression is used to re-establish a new hierarchical order. If repeated changes in group composition occur, persistent aggression may arise, sometimes leading to physical injury and acute stress. A tryptophan-enriched diet may help producers avoid these problems, especially when groups of pigs are mixed together. This research was published in the January 31, 2010 issue of Applied Animal Behaviour Science. [Press release]

Hood Keynote Highlights Conference on Future of Genomic Medicine

In the keynote address to 300 attendees at the Future of Genomic Medicine III conference in La Jolla, California (March 5-6, 2010), Dr. Leroy Hood, President of the Institute for Systems Biology, sketched his optimistic vision of the future of personalized DNA-based medicine, and predicted that within five years it will be possible to sequence an entire human genome in under an hour for a cost of $500 or less. He emphasized the importance of taking a systems approach to biological investigations and described how such an approach had been applied to the analysis of prion disease in a mouse model. Dr. Hood also outlined the first-ever full genome sequencing of a complete family of two children and both parents, in which both children had inherited the same two rare recessive genetic diseases (Miller’s syndrome and primary ciliary dyskinesia), but both parents were unaffected. The analysis of the four complete sequences revealed the two disease genes that were inherited by both affected children. Dr. Hood noted that the ability to compare all four related sequences allowed for a significant increase in sequencing accuracy. Dr. Hood also envisioned a future of individual patients surrounded by clouds of data points that might prove key to their individual diagnoses and therapies, and he emphasized that biology is an informational science. He noted that the management and interpretation of data will be crucial going forward. He said that a critical goal for medical genetic tests is that they be both predictive and actionable. Dr. Hood was just one of many luminaries who took to the podium at this year’s conference, hosted by the Scripps Translational Science Institute and the J. Craig Venter Institute, and sponsored by a number of major biotech and pharmaceutical companies.

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