A growing amount of research is finding that smoke-free air laws help smokers quit or reduce the amount that they smoke. Rather than changing smokers’ own attitudes about smoking, the influence of the policies, particularly the strong ones, might lie more in changing smokers’ perceptions of other people’s attitudes about smoking — changing the perceived social norms, according to an Indiana University study involving smoke-free air laws in four Texas communities. “Everyone knows it’s unhealthy to smoke,” said Jon Macy, the study’s lead researcher. “Our study suggests that the success of strong smoke-free air policies may be more about changing the social acceptability of smoking.” The IU study used a telephone survey of 407 adults to compare perceived norms about smoking between adults living in two cities with strong smoke-free air laws and adults living in two cities with weak smoke-free air laws. Those who lived in cities with a strong smoke-free air law perceived a lower prevalence of smoking in their city, were less likely to report that other people in their city believed smoking was acceptable, and were more likely to report that people in their city believed that smokers should take measures to not smoke. Macy said that while researchers are aware that smoke-free air policies, which are designed primarily to protect the public from the harm of secondhand tobacco smoke, also influence smoking behavior, the mechanism or cause has not been nailed down. This study offers one possible explanation. Macy said insights provided by this study could help with public communication messages that accompany smoke-free air policies. The messages, for example, could tap into the impact societal norms have on smoking behavior.

Researchers at National Jewish Health have identified a simple gene-based blood test that more accurately and quickly measures cystic fibrosis patients’ response to therapy than current tests. The test, a measure of inflammatory gene expression, could improve patient care and help clear a backlog of promising medications now hung up in clinical trials. The researchers are publishing the results of a small “proof-of-principal” trial in the November 1, 2008, issue of American Journal of Respiratory and Critical Care Medicine .

“The currently accepted test, a measure of a patients’ ability to exhale air, has several limitations that make it ineffective for some patients and not sensitive enough for clinical trials of many new medications,” said Dr. Milene Saavedra, lead author of the study and Assistant Professor of Medicine at National Jewish Health. “By measuring the activity of genes associated with the immune/inflammatory response, we can get a more accurate picture of the biological processes occurring inside the lungs.”

Cystic fibrosis is the most common lethal inherited disease in the western world, with about 30,000 patients in the US . Most patients die of respiratory failure generally in their 30s or 40s. Lung damage is caused primarily by chronic bacterial infections and the resulting severe airway inflammation. There is a critical need for new effective anti-microbial and anti-inflammatory medications to slow and/or prevent lung damage in young patients. Several promising therapies have gone through early stages of clinical testing but their progress is being hampered by the lack of a sensitive measure of therapeutic response to medications.

Currently, response to medication is measured by how much air a person can rapidly exhale: forced expiratory volume in one second or FEV1. FEV1 cannot be performed effectively for all patients, especially young and very sick patients. Generally patients’ FEV1 does improve when inflammation is reduced, but not all patients’ FEV1 improves significantly, and changes can take weeks to months to show up. It can be prohibitively expensive to conduct phase 2 or phase 3 trials of medications long enough to detect the changes in FEV1.

National Jewish researchers thought white blood cells circulating in the blood might be a good source of biomarkers for a more sensitive and accurate test. White blood cells are the predominant cell type at sites of tissue destruction in CF patients’ lungs. As they circulate through the lungs in the blood they encounter the inflammatory environment and alter their gene expression as a result. By measuring mRNA, scientists can identify which genes are being expressed and how strongly.

The researchers evaluated 18 CF patients who were suffering severe exacerbations of their disease. They withdrew blood before and after two weeks of intravenous antibiotic therapy. The severe exacerbation and antibiotic therapy served as a condensed model of illness and response to therapy; in these cases antibiotic therapy is usually successful, and patients’ clinical symptoms and FEV1 both improve rapidly.

Using microarray gene analysis of the blood samples, the researchers identified 10 genes that differed significantly in their expression before and after therapy. Using real-time polymerase chain reaction and additional statistical tools, the researchers identified three of those genes that most accurately correlated with a positive therapeutic response: CD36, CD64 and ADAM9. CD36 and CD64 are genes associated with cells’ absorption of foreign organisms and cellular debris. ADAM9 is associated with tissue destruction that allows inflammatory cells to move through tissue. This process is also believed to contribute to permanent tissue destruction.

“The expression of these genes correlated with FEV1, other inflammatory markers, and various clinical factors,” said co-author Dr. Jerry Nick , Associate Professor of Medicine at National Jewish. “When combined with FEV1, they offered a more accurate and sensitive measure of response to therapy than either alone. We believe they could be extremely useful in clinical care of patients and trials of new CF therapies.”

The researchers are now conducting a trial of 60 CF patients to provide stronger statistical evidence for the power of CD36, CD64 and ADAM9 to diagnose a positive response to therapy by CF patients.

Researchers at National Jewish Health are testing an investigational treatment to learn if poking holes in the lungs of emphysema patients can immediately help them breathe more easily. Destruction of lung tissue caused by emphysema can leave lungs stiff and overinflated with air that cannot escape. The holes, kept open by small stents inserted during a minimally invasive procedure, could relieve the hyperinflation of the lungs, allowing the healthy parts of the lungs to more easily inflate and take in air.

“Advanced emphysema patients are often in poor physical condition, struggling with each breath,” said Ali Musani, MD, FCCP, principal investigator of the study at National Jewish. “If patients can breathe easier it is likely to improve their quality of life.”

During the airway bypass procedure, new openings are created in the airway wall connecting the damaged lung tissue to the natural airway. These pathways are supported and kept open by Exhale® Drug-Eluting Stents – manufactured by Broncus Technologies, Inc.

“Airway bypass is groundbreaking because right now it is the only treatment being studied to help emphysema patients whose disease has destroyed tissue throughout the lung,” said Dr. Musani. “If successful this minimally invasive procedure would help those who would not otherwise be considered for or benefit from lung volume reduction surgery.”

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is a chronic, progressive and irreversible lung disease characterized by the destruction of lung tissue. The loss of the lungs’ natural elasticity and the collapse of airways in the lung combine to make exhalation ineffective, leaving emphysema sufferers with hyperinflation because they are unable to get air out of their lungs. Breathing becomes inefficient and patients have to work very hard just to breathe.

National Jewish is currently recruiting patients for the EASE trial. The study will last from 15 months to 5 years, depending if the patient is randomized to the control or the treatment group. During the airway bypass procedure physicians will use a Doppler probe inserted through the bronchoscope to identify a site in the airway that is away from blood vessels. A special needle is then used to make a small opening and an Exhale-Drug-Eluting-Stent is placed in the passageway to keep it open. The procedure involves placing up to six drug-eluting stents.

Although this procedure is still under clinical investigation, feasibility data suggest it may hold promise for patients with emphysema. Results from the feasibility study were published in the October 2007 issue of the Journal of Throacic and Cardiovascular Surgery. Positive results included a statistically significant reduction in the amount of air trapped in the lungs and an improvement in breathing for patients at six months after the airway bypass procedure.

“Given that emphysema, which permanently destroys lung function, is such a devastating disease, any potential new treatment option could offer substantial relief to the millions who suffer,” said Dr. Musani.

Working as part of a multi-institutional collaboration, scientists at Washington University School of Medicine in St. Louis have assembled the most complete catalog to date of the genetic changes underlying the most common form of lung cancer.  The research, published Oct. 23 in Nature, helps lay the foundation for more personalized diagnosis and treatment of a disease that is the leading cause of U.S. cancer deaths.

The research team identified 26 genes that are frequently mutated in a type of cancer called lung adenocarcinoma, a finding that more than doubles the number of genes already known to be linked to the deadly disease.  What’s more, by casting a wide net in their search for genetic alterations, the scientists are now beginning to see intriguing relationships.  They found that some of the same genes associated with lung tumors are also defective in other cancers, that smokers and non-smokers with lung cancer have distinct genetic defects and that several molecular pathways underlie most of the mutations.

“This genomic approach has given us a completely different view of lung cancer,” says Richard K. Wilson, Ph.D., director of Washington University’s Genome Sequencing Center and one of the study’s lead authors.  “This broad view will allow scientists to more accurately categorize tumors, which should speed efforts to develop more targeted therapies to fight the disease.”

More than 1 million people worldwide die of lung cancer each year, including more than 160,000 in the United States.  About 40 percent of them are adenocarcinoma, a type of non-small cell lung cancer and one that is exceedingly difficult to treat.  Only about 15 percent of patients are still alive five years after diagnosis.

“By harnessing the power of genomic research, this pioneering work has painted the clearest and most complete portrait yet of lung cancer’s molecular complexities,” says Alan E. Guttmacher, M.D., acting director of the National Human Genome Research Institute, the agency that funded the research.

The Nature study was conducted as part of the Tumor Sequencing Project, a collaborative effort to assemble a genome-wide catalog of the genetic mutations in lung adenocarcinoma.  Like most cancers, lung adenocarcinoma arises from changes that accumulate in people’s DNA over the course of their lives.  However, little is known about the precise nature of these genetic alterations, how they occur and how they disrupt biological pathways to cause cancer’s unfettered cell growth.

Working with lung cancer samples donated by 188 patients from across the United States, the group sequenced 623 suspect genes and compared them to the same genes in healthy tissues from the same patients.  Initially, they found more than 1,000 mutations across the samples.  Looking more closely, the researchers identified 26 genes mutated in a significant number of samples.  Most of the genes had not previously been associated with lung cancer but are found in other tumors.

The new genes fingered in lung adenocarcinoma include:

* Neurofibromastosis 1: Mutations in this gene cause a rare inherited neurological disorder that increases the risk of tumors that form on nerve tissues, including the brain, spinal cord and individual nerves;

* Ataxia telangiectasia mutated (ATM): Mutations of this gene have been found in a rare inherited neurological disorder and in various types of leukemia and lymphoma;

* Retinoblastoma 1: Mutations in this gene have linked to a rare childhood cancer that begins in the retina;

* Adenomatosis polyposis coli (APC): Mutations of this gene are common in colon cancer.

The team also examined the effects of the genetic mutations on biological pathways and determined which of the pathways is most crucial to lung adenocarcinoma.  This line of discovery is essential to efforts to develop new and better treatments for cancer.

For example, the researchers discovered that more than 70 percent of the 188 tumors had at least one mutation affecting the mitogen-activated protein kinase (MAPK) pathway, indicating it plays a pivotal role in lung cancer.  Based on those findings, the researchers suggested new treatment strategies for some subtypes of lung adenocarcinoma might include compounds that affect this pathway.  One such group of compounds, the MEK inhibitors, has produced promising results in mouse models of lung cancer.

“Looking at the pathways helps simplify the picture,” Wilson explains.  “Generally, we found that each mutation only occurs in a small percentage of the tumor samples, but when we looked at all the mutations that intersect a particular signaling pathway, we were surprised to find a lot of overlap in only a handful of pathways.  This gives us a much better idea of what goes wrong in cells when they become cancerous.”

Additionally, the finding that more than 30 percent of tumors had mutations affecting the rapamycin (mTOR) pathway raises the possibility that the drug rapamycin might be tested in lung adenocarcinoma.  The drug, which inhibits mTOR, is approved for use in organ transplants and renal cancer.

The researchers also analyzed the patterns of genetic changes in both smokers and non-smokers with lung cancer.  About 90 percent of lung cancer is linked to smoking, but 10 percent of patients diagnosed with the disease have never smoked.  They found that the number of mutations detected in tumor samples from smokers was significantly higher than in tumors from never-smokers.  Smokers’ tumors contained as many as 49 mutations, while none of the never-smokers’ tumors had more than five.

More work is needed to determine the clinical significance of these differences.  However, doctors do know that in some other types of cancer, high mutation levels may cause a tumor to spread rapidly or be resistant to treatment.

The study also confirmed previous observations that indicated lung cancer in never-smokers may be triggered by different genetic mutations than those in smokers.  For example, mutations in the epidermal growth factor (EGFR) gene were prevalent in tumors from non-smokers, while mutations in the KRAS and Src tyrosine kinase 11 genes were common in tumors from smokers.

“Our findings underscore the value of systematic, large-scale genome studies for exploring cancer.  We now must move forward to apply this approach to even larger groups of samples and a wider range of cancers,” Wilson says.

Asthma sufferers who regularly take the beta2-agonist formoterol are more likely to suffer non-fatal serious adverse events than those given placebos.  A review carried out by Cochrane Researchers showed a significantly increased risk for people who took the drug once or twice daily for at least 12 weeks.

Long-acting beta2-agonists are inhaled to help open the airways and last for 12 hours or more, but their long-term use is controversial.  Recent research has cast doubt on the safety of salmeterol.  Now researchers are calling into question the safety of the related drug formoterol.

“Our findings are similar to those of a review published earlier this year, which found that regular salmeterol causes an increase in non-fatal adverse events,” says lead researcher of both studies, Christopher Cates, who works in Community Health Sciences at St George’s, London.

22 studies involving 8,032 people diagnosed with asthma were included in the latest review.  In those studies that compared formoterol to a placebo, 16 patients per thousand taking formoterol suffered serious adverse effects, whilst only 10 per thousand taking placebos were similarly affected.  Serious adverse effects were most commonly asthma–related.  The increase in adverse events was more marked in younger patients.

“It is possible that children are at a higher risk of suffering serious effects due to this drug, but we can’t say for sure.  We would urge that all serious adverse events are more fully reported in medical journals so that we can make a better assessment of drug safety,” says Cates.

Individuals with a number of clinical conditions, including pneumonia, and those treated by mechanical ventilation for a prolonged period of time are at risk of acute lung injury, a life-threatening disorder for which there is no treatment. It is hoped that understanding the natural processes by which acute lung injury spontaneously resolves in some individuals might provide new therapeutic targets. Thus, Holger Eltzschig and colleagues, at the University of Colorado Health Sciences Center, Denver, suggest that their observation in mice with ventilator-induced lung injury (VILI) implicate the protein A2BAR as a potential therapeutic target for acute lung injury.

In the study, mice lacking A2BAR were found to have reduced survival time and more severe VILI, when compared with normal mice. Consistent with this, normal mice treated with an A2BAR antagonist exhibited more severe lung damage than untreated mice, whereas an A2BAR agonist attenuated the severity of VILI. Further analysis revealed that one way in which the A2BAR agonists helped was by enhancing the clearance of fluid in the lungs (i.e., they helped dry out the lungs). These data indicate that agonists of A2BAR are likely to be part of the natural mechanism by which acute lung injury spontaneously resolves and might make good therapeutics.

New insight into how pollution and cigarette smoke damage airways has been provided by Pierangelo Geppetti and colleagues, at the University of Florence, Italy, who studied the effects of such chemicals on guinea pig airways.  As discussed, in an accompanying commentary, by Sidney Simon and Wolfgang Liedtke, at Duke University Medical Center, it is hoped that this information will help in the development of therapeutics to combat the effects of pollutants and perhaps help individuals with smoke-related diseases such as chronic obstructive pulmonary disease and chronic asthma.

In the study, chemicals found in cigarette smoke were shown to activate signaling in nerves that ended in the airways of guinea pigs.  These effects were abolished using a molecule that inhibited a protein known as TRPA1.  Consistent with a central role for TRPA1 in sensing chemicals in cigarette smoke, no signaling in nerves that end in the airways was observed in mice lacking TRPA1 after exposure to the chemicals in cigarette smoke.  Further analysis showed that alpha,beta-unsaturated aldehydes were the chemicals that activated TRPA1, suggesting that they might contribute to the airway damage that occurs in smoke-related diseases.