Lung Cancer Risk after Exposure to Polycyclic Aromatic Hydrocarbons: A Review and Meta-Analysis

Typical polycyclic aromatic hydrocarbon mixtures are established lung carcinogens, but the quantitative exposure–response relationship is less clear. To clarify this relationship we conducted a review and meta-analysis of published reports of occupational epidemiologic studies. Thirty-nine cohorts were included. The average estimated unit relative risk (URR) at 100 μg/m(3) years benzo[a]pyrene was 1.20 [95% confidence interval (CI), 1.11–1.29] and was not sensitive to particular studies or analytic methods. However, the URR varied by industry. The estimated means in coke ovens, gasworks, and aluminum production works were similar (1.15–1.17). Average URRs in other industries were higher but imprecisely estimated, with those for asphalt (17.5; CI, 4.21–72.78) and chimney sweeps (16.2; CI, 1.64–160.7) significantly higher than the three above. There was no statistically significant variation of URRs within industry or in relation to study design (including whether adjusted for smoking), or source of exposure information. Limited information on total dust exposure did not suggest that dust exposure was an important confounder or modified the effect. These results provide a more secure basis for risk assessment than was previously available

Maximum-Entropy Weighting of Multi-Component Earth Climate Models

A maximum entropy-based framework is presented for the synthesis of projections from multiple Earth climate models. This identifies the most representative (most probable) model from a set of climate models -- as defined by specified constraints -- eliminating the need to calculate the entire set. Two approaches are developed, based on individual climate models or ensembles of models, subject to a single cost (energy) constraint or competing cost-benefit constraints. A finite-time limit on the minimum cost of modifying a model synthesis framework, at finite rates of change, is also reported.Comment: Inspired by discussions at the Mathematical and Statistical Approaches to Climate Modelling and Prediction workshop, Isaac Newton Institute for Mathematical Sciences, Cambridge, UK, 11 Aug. to 22 Dec. 2010. Accepted for publication in Climate Dynamics, 8 August 201

From where did the 2009 'swine-origin' influenza A virus (H1N1) emerge?

The swine-origin influenza A (H1N1) virus that appeared in 2009 and was first found in human beings in Mexico, is a reassortant with at least three parents. Six of the genes are closest in sequence to those of H1N2 'triple-reassortant' influenza viruses isolated from pigs in North America around 1999-2000. Its other two genes are from different Eurasian 'avian-like' viruses of pigs; the NA gene is closest to H1N1 viruses isolated in Europe in 1991-1993, and the MP gene is closest to H3N2 viruses isolated in Asia in 1999-2000. The sequences of these genes do not directly reveal the immediate source of the virus as the closest were from isolates collected more than a decade before the human pandemic started. The three parents of the virus may have been assembled in one place by natural means, such as by migrating birds, however the consistent link with pig viruses suggests that human activity was involved. We discuss a published suggestion that unsampled pig herds, the intercontinental live pig trade, together with porous quarantine barriers, generated the reassortant. We contrast that suggestion with the possibility that laboratory errors involving the sharing of virus isolates and cultured cells, or perhaps vaccine production, may have been involved. Gene sequences from isolates that bridge the time and phylogenetic gap between the new virus and its parents will distinguish between these possibilities, and we suggest where they should be sought. It is important that the source of the new virus be found if we wish to avoid future pandemics rather than just trying to minimize the consequences after they have emerged. Influenza virus is a very significant zoonotic pathogen. Public confidence in influenza research, and the agribusinesses that are based on influenza's many hosts, has been eroded by several recent events involving the virus. Measures that might restore confidence include establishing a unified international administrative framework coordinating surveillance, research and commercial work with this virus, and maintaining a registry of all influenza isolates

Finding the needle in the haystack: why high-throughput screening is good for your health

High-throughput screening is an essential component of the toolbox of modern technologies that improve speed and efficiency in contemporary cancer drug development. This is particularly important as we seek to exploit, for maximum therapeutic benefit, the large number of new molecular targets emerging from the Human Genome Project and cancer genomics. Screening of diverse collections of low molecular weight compounds plays a key role in providing chemical starting points for iterative optimisation by medicinal chemistry. Examples of successful drug discovery programmes based on high-throughput screening are described, and these offer potential in the treatment of breast cancer and other malignancies

Malignant mesothelioma

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis

Identifying Changes in Selective Constraints: Host Shifts in Influenza

The natural reservoir of Influenza A is waterfowl. Normally, waterfowl viruses are not adapted to infect and spread in the human population. Sometimes, through reassortment or through whole host shift events, genetic material from waterfowl viruses is introduced into the human population causing worldwide pandemics. Identifying which mutations allow viruses from avian origin to spread successfully in the human population is of great importance in predicting and controlling influenza pandemics. Here we describe a novel approach to identify such mutations. We use a sitewise non-homogeneous phylogenetic model that explicitly takes into account differences in the equilibrium frequencies of amino acids in different hosts and locations. We identify 172 amino acid sites with strong support and 518 sites with moderate support of different selection constraints in human and avian viruses. The sites that we identify provide an invaluable resource to experimental virologists studying adaptation of avian flu viruses to the human host. Identification of the sequence changes necessary for host shifts would help us predict the pandemic potential of various strains. The method is of broad applicability to investigating changes in selective constraints when the timing of the changes is known

Functional Comparison of Innate Immune Signaling Pathways in Primates

Humans respond differently than other primates to a large number of infections. Differences in susceptibility to infectious agents between humans and other primates are probably due to inter-species differences in immune response to infection. Consistent with that notion, genes involved in immunity-related processes are strongly enriched among recent targets of positive selection in primates, suggesting that immune responses evolve rapidly, yet providing only indirect evidence for possible inter-species functional differences. To directly compare immune responses among primates, we stimulated primary monocytes from humans, chimpanzees, and rhesus macaques with lipopolysaccharide (LPS) and studied the ensuing time-course regulatory responses. We find that, while the universal Toll-like receptor response is mostly conserved across primates, the regulatory response associated with viral infections is often lineage-specific, probably reflecting rapid host–virus mutual adaptation cycles. Additionally, human-specific immune responses are enriched for genes involved in apoptosis, as well as for genes associated with cancer and with susceptibility to infectious diseases or immune-related disorders. Finally, we find that chimpanzee-specific immune signaling pathways are enriched for HIV–interacting genes. Put together, our observations lend strong support to the notion that lineage-specific immune responses may help explain known inter-species differences in susceptibility to infectious diseases

Highly pathogenic avian influenza virus infection in chickens but not ducks is associated with elevated host immune and pro-inflammatory responses

Highly pathogenic avian influenza (HPAI) H5N1 viruses cause severe infection in chickens at near complete mortality, but corresponding infection in ducks is typically mild or asymptomatic. To understand the underlying molecular differences in host response, primary chicken and duck lung cells, infected with two HPAI H5N1 viruses and a low pathogenicity avian influenza (LPAI) H2N3 virus, were subjected to RNA expression profiling. Chicken cells but not duck cells showed highly elevated immune and pro-inflammatory responses following HPAI virus infection. HPAI H5N1 virus challenge studies in chickens and ducks corroborated the in vitro findings. To try to determine the underlying mechanisms, we investigated the role of signal transducer and activator of transcription-3 (STAT-3) in mediating pro-inflammatory response to HPAIV infection in chicken and duck cells. We found that STAT-3 expression was down-regulated in chickens but was up-regulated or unaffected in ducks in vitro and in vivo following H5N1 virus infection. Low basal STAT-3 expression in chicken cells was completely inhibited by H5N1 virus infection. By contrast, constitutively active STAT-3 detected in duck cells was unaffected by H5N1 virus infection. Transient constitutively-active STAT-3 transfection in chicken cells significantly reduced pro-inflammatory response to H5N1 virus infection; on the other hand, chemical inhibition of STAT-3 activation in duck cells increased pro-inflammatory gene expression following H5N1 virus infection. Collectively, we propose that elevated pro-inflammatory response in chickens is a major pathogenicity factor of HPAI H5N1 virus infection, mediated in part by the inhibition of STAT-3