Genetic components of dendritic cells key to asthma and allergy-related immune response function have been identified by researchers in Pittsburg (PA, USA). Understanding the genetics behind the stages of the hyperimmune response is important for identifying new targets for drug development, ultimately resulting in better treatment for asthma.
It is well documented that dendritic cells are involved in the recognition and capture of potential pathogens in order that they be destroyed by T lymphocytes. In this study, the authors have highlighted a pathway that allows dendritic cells to respond directly to allergens in order to evoke the T-lymphocyte response. The identified molecule is c-Kit. Anuradha Ray, Professor of medicine and immunology, explains, “We show that genes encoding for c-Kit and the cytokine IL-6 are significantly activated when allergens are present, but c-Kit is the very first molecule that gets triggered.”
The researchers made their discovery by studying the response of dendritic cells cultured from c-Kit-mutant mice to invasion by cholera toxin and a standard allergen, house dust mites. Both molecules induced significant secretion of c-Kit and IL-6, resulting in a cascade leading to the activation of T lymphocytes.
Prabir Ray, corresponding author of the study, is hopeful that their discovery will lead to new therapy for asthma, “Therapy directed against c-Kit specifically on dendritic cells using compounds coupled to c-Kit inhibitors such as Gleevec®, a drug that is already FDA-approved and used in cancer treatment, may alleviate allergic diseases and, potentially, inflammatory bowel disease.”
Inhibition of c-Kit also has potential to treat cancers where dual upregulation of c-Kit and stem cell factor has been observed, which includes small-cell lung cancer.
Source: Krishnamoorthy N, Oriss TB, Paglia M et al. Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat. Med. 14, 565–573 (2008).
Rapid diagnosis of TB to be investigated
A group of scientists from Cranfield University (UK) in collaboration with the London School of Hygiene and Tropical Medicine have made plans to develop new methods for the rapid diagnosis of TB in humans. Current methods of diagnosis are time consuming as samples need to be processed in laboratories, which may also be inconvenient for communities not near such facilities.
The collaboration intend to look for volatile marker compounds present and absent in patient blood and sputum and cultures of the TB bacteria. Any potential TB biomarkers identified will be searched for in volatile gases, such as breath. The scientists’ vision is for the resulting data to be programmed into existing portable devices that can search specifically for TB. Claire Turner, Head of the Volatiles Research Group believes breath will eventually be the most effective, convenient and least-invasive method for testing TB, and comments, “Early indications show that a lot more work needs to be done first to find these important compounds. We are seeking further collaboration from other interested parties to help us put our plans into action.”
A third of the world’s population is reported to be infected with TB and the disease is spreading through Europe and the USA. Furthermore, the emergence of multidrug-resistant (MDR)-TB has heightened the need for the development of a method to detect TB rapidly, since, during the time of diagnosis, a patient with MDR-TB is likely to infect those they have come into contact with or succumb to the infection themselves.
MDR-TB often results from patients not finishing their course of treatment or when the wrong or incomplete combination of drugs has been prescribed. Incomplete treatment often occurs in poor countries since patients fail to understand the importance of finishing their prescription, patients are unable to get to the clinic or the drugs become unavailable.
Ruth McNerney from the London School of Hygiene and Tropical Medicine explains, “We are in desperate need of new technologies to detect TB disease. The current frontline test that looks for the bacteria in sputum specimens using a microscope was developed over 100 years ago. It is labor intensive and insensitive and less than half of the nine million new cases of TB each year are successfully diagnosed in this way”.
Source: www.cranfield.ac.uk
Low dietary magnesium may be a risk factor for lung cancer
DNA repair capacity has been linked with dietary magnesium in a study conducted by epidemiologists at the MD Anderson Cancer Center (TX, USA). Although it has been documented that magnesium has a role in the maintenance of genomic stability, less data on the relationship between dietary intake and lung cancer are available. In the lung cancer case–control study, 1139 cases and 1210 matched healthy controls that had data on both diet and DNA repair capacity (DRC) participated. A modified Block-NCI Food Frequency Questionnaire was used to assess dietary intake. DRC was determined, using the host cell reactivation assay, by the ability of the sample to repair in lymphocyte cultures.
After adjusting for potential confounding factors, such as DRC, the odds ratios and 95% confidence intervals for lung cancer decreased with increasing levels of dietary magnesium. This relationship was statistically significant (p < 0.0001).
The scientists also investigated the histology and clinical stage of lung cancer. Reduced DRC and an increased risk of lung cancer were found to be associated with low intake of dietary magnesium. Both male and female participants with high dietary magnesium intake and efficient DRC were less likely to have lung cancer than those with low dietary magnesium intake and reduced DRC. The effect of dietary magnesium intake and DRC was more pronounced among participants aged over 60 years, current or heavier smokers, those with a family history of cancer in first-degree relatives, small-cell lung cancer and late-stage disease. The authors commented, “These intriguing results need to be confirmed in prospective studies.”
Source: Mahabir S, Wei Q, Barrera SL et al. Dietary magnesium and DNA repair capacity as risk factors for lung cancer. Carcinogenesis (2008) Epub ahead of print.
Further insight into the role of TNF in airflow obstruction
A study has provided further evidence to suggest that TNF is linked with chronic obstructive pulmonary disease (COPD). Results from previous research in humans have so far been inconclusive, despite animal models indicating an importance for TNF in COPD.
The study, published in the European Respiratory Journal, recruited 423 Caucasian smokers, 298 with spirometric evidence of COPD and 125 without airflow obstruction. Six TNF single-nucleotide polymorphisms with biologic activity and their haplotypes were analyzed. Multivariate analysis revealed that the -308 minor allele had an odds ratio (OR) of 1.9 (95% confidence interval [CI]: 1.1–3.2) of being associated with COPD, where the -237 minor allele had a lower incidence, with an OR of 0.40 (95% CI: 0.19–0.86). The -308 minor allele was associated with worse forced expiratory volume in 1 s and forced vital capacity.
The -857 minor allele had a lower OR of being associated with severe stages of COPD (OR: 0.46; 95% CI: 0.24–0.88). No other TNF single-nucleotide polymorphism was found to be associated with COPD in the study. The authors, from Denver (CO, USA) conclude that, “The present study adds further evidence that tumor necrosis factor genotypes play a role in susceptibility to cigarette smoke.”
Source: Gingo MR, Silveira LJ, Miller YE et al. Tumour necrosis factor gene polymorphisms are associated with COPD. Eur. Respir. J. 31, 1005–1012 (2008).
New lung imaging technique for the diagnosis of lung disease
Previously unattainable images of lung ventilation have been obtained using the signal of inhaled hyperpolarized noble gases with innovative technology, developed by scientists at the University of Sheffield, UK. Hyperpolarized gas MRI gives high spatial and temporal resolution images of gas ventilation in the lungs in addition to functional information. The hope is that use of this technology will result in earlier diagnosis of lung conditions such as emphysema and smoking-related damage.
The patient inhales small harmless amounts of hyperpolarized noble gases, such as Helium-3 and Xenon-129, while an MRI scanner is used to generate the image. The gases are hyperpolarized using high-power lasers by a process called optical pumping.
The use of this imaging technique is promising, with early clinical trials detecting the early stages of lung obstruction in children with cystic fibrosis, something an x-ray would miss. Tests carried out in smokers have revealed signs of early emphysema. In addition to providing clinicians with further anatomical and functional information, the new technique does not have the safety concerns that come with x-ray imaging.
Source: www.shef.ac.uk/medicine/research
Airway responses to asthma attack in obese and nonobese women
A study investigating the differences in asthma severity between obese and nonobese women has concluded that the changes in respiratory functions in obese patients are greater.
This study is the first prospective study to report a significant difference between airway response to an asthma attack between obese and nonobese patients. Such studies are increasingly necessary, in view of the fact that, according to the WHO, 400 million people in the world were obese in 2005 and this figure is predicted to rise to 700 million by 2015.
Bronchoconstriction, which occurs during an asthma attack, invokes changes in airway caliber and lung volumes; the researchers, based in New Zealand, aimed to determine if these changes are the same in obese and nonobese asthmatic patients. Nebulized methacholine was administered to 30 female subjects to induce bronchoconstriction, with the aim of reducing the forced expiratory volume in 1 s by 30%. To assess any differences among the subjects, spirometry, lung volume and dyspnea scores were obtained before and immediately after the inducement of bronchoconstriction.
Obese subjects were reported to have significantly greater increases in functional residual capacity and decreases in inspiratory capacity (p < 0.001 and p = 0.003, respectively). Obesity was defined by the BMI of the participant and the results were adjusted to take into account baseline airway caliber and hyperresponsiveness. The results provide evidence for a link between obesity and ‘dynamic hyperinflation’, which occurs when obstructions in the lung reduce the flow of air out of the lungs. Dynamic hyperinflation can be treated by surgery, physically increasing external resistance to reduce respiratory rate or pharmacologic treatment. Robin Taylor, author of the study, comments, “This means that among women with greater BMI, an asthma-like episode has the potential to cause greater breathing difficulties than in non-obese women.”
The authors conclude that, “Changes in respiratory function, notably dynamic hyperinflation, are greater in obese individuals with bronchoconstriction. This may potentially alter the perception and assessment of asthma severity in obese patients with asthma.”
Source: Sutherland TJT, Cowan JO, Taylor DR. Dynamic hyperinflation with bronchoconstriction: differences between obese and nonobese women with asthma. Am. J. Respir. Crit. Care Med. 177, 970–975 (2008).
New tool to help oncologists treat lung cancer
A free, online database of EGF receptor (EGFR) mutations has been launched to help clinicians find optimum treatment for non-small-cell lung cancer patients.
A pioneering lung cancer mutation database has been developed by researchers at the Department of Molecular Pathology and Translational Oncology at the Metropolitan Hospital, Athens, Greece. It was launched at the 1st European Lung Cancer Conference held in Geneva, Switzerland.
The first version of the database contains details of 3305 somatic mutations in the EGFR that all relate to non-small-cell lung cancer. Crucially for clinical oncologists, the database contains exon-specific mutational spectrum correlated with tyrosine kinase inhibitor (TKI) treatment-related responses. This information will be of use when assessing which therapy is best for their patient, since somatic mutations in this receptor molecule affect the effectiveness of treatment with TKIs. The database catalogues 254 different mutations. This includes 12,244 patients, of whom 3381 had somatic mutations in EGFR.
Samuel Murray from the Metropolitan Hospital, Athens, Greece, comments, “We have known for some time that some EGFR mutations correlate with response to tyrosine kinase inhibitors for lung cancer patients, but there have been so many articles published on this topic that we felt that it would be virtually impossible for any given center or individual to interpret the clinical relevance of a given mutation. So we worked on the assumption that a comprehensive list of all somatic EGFR mutations coupled with data on the response of non-small-cell lung cancers treated with tyrosine kinase inhibitors would help clinicians determine whether a specific mutation was likely to correlate with clinical benefit.”
Source: www.somaticmutations-EGFR.org