Potential role of bioactive lipids in the development of non-antibody mediated transfusion-related acute lung injury (TRALI)

Transfusion-related acute lung injury (TRALI) has been the leading cause of transfusion-related morbidity and mortality in the UK and the USA in recent years. A threshold mechanism of TRALI has been proposed in which both patient factors (type and/or severity of clinical insult) and blood product factors (strength and/or concentration of antibodies or biological response modifiers) interact to surpass a threshold for TRALI development (Bux et al. Br J Haematol; 2007; 136: 788-99). The risk of developing antibody-mediated TRALI has been minimised by the introduction of risk-reduction strategies such as limiting the use of plasma from female donors. In contrast, there are no strategies currently in place to mitigate the development of non-antibody mediated TRALI as the mechanisms remain largely undefined. Previous studies have implicated non-polar lipids such as arachidonic acid and various species of hydroxyeicosatetranoic acid (HETE) in the development of non-antibody mediated TRALI (Silliman et al. Transfusion; 2011; 51: 2549-54), however the contribution of these lipids to the development of an inflammatory response in TRALI is poorly understood.

Inferring lung cancer risk factor patterns through joint Bayesian spatio-temporal analysis

Background: Preventing risk factor exposure is vital to reduce the high burden from lung cancer. The leading risk factor for developing lung cancer is tobacco smoking. In Australia, despite apparent success in reducing smoking prevalence, there is limited information on small area patterns and small area temporal trends. We sought to estimate spatio-temporal patterns for lung cancer risk factors using routinely collected population-based cancer data. Methods: The analysis used a Bayesian shared component spatio-temporal model, with male and female lung cancer included separately. The shared component reflected exposure to lung cancer risk factors, and was modelled over 477 statistical local areas (SLAs) and 15 years in Queensland, Australia. Analyses were also run adjusting for area-level socioeconomic disadvantage, Indigenous population composition, or remoteness. Results: Strong spatial patterns were observed in the underlying risk factor exposure for both males (median Relative Risk (RR) across SLAs compared to the Queensland average ranged from 0.48-2.00) and females (median RR range across SLAs 0.53-1.80), with high exposure observed in many remote areas. Strong temporal trends were also observed. Males showed a decrease in the underlying risk across time, while females showed an increase followed by a decrease in the final two years. These patterns were largely consistent across each SLA. The high underlying risk estimates observed among disadvantaged, remote and indigenous areas decreased after adjustment, particularly among females. Conclusion: The modelled underlying exposure appeared to reflect previous smoking prevalence, with a lag period of around 30 years, consistent with the time taken to develop lung cancer. The consistent temporal trends in lung cancer risk factors across small areas support the hypothesis that past interventions have been equally effective across the state. However, this also means that spatial inequalities have remained unaddressed, highlighting the potential for future interventions, particularly among remote areas.

Toward making inroads in reducing the disparity of lung health in Australian Indigenous and New Zealand Maori children

Globally, Indigenous populations, which include Aboriginal and Torres Strait islanders in Australia and Māori people in New Zealand (NZ), have poorer health than their non-Indigenous counterparts (1). Indigenous peoples worldwide face substantial challenges in poverty, education, employment, housing, and disconnection from ancestral lands (1). While addressing social determinants of health is a priority, solving clinical issues is equally important. Indeed, ignoring the latter until social issues improve risks further disparity as this may take generations. A systematic overview of interventions addressing social determinants of health found a striking lack of reliable evaluations (2). Where evidence was available, health improvement associated with interventions was modest or uncertain (2). Thus, advances in healthcare remain essential and these require the best evidence available in preventing and managing common illnesses, including respiratory illnesses

Telomere length in circulating leukocytes is associated with lung function and disease

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= −0.0452, p=0.024) as well as COPD (β= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

The role of DNA repair pathways in cisplatin resistant lung cancer

Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.

Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer

Background The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process. Methods NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells. Results Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls. Conclusions Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.

DNA repair pathways and their therapeutic potential in lung cancer

Lung cancer is the leading cause of cancer-related mortality. According to WHO, 1.37 million deaths occur globally each year as a result of this disease. More than 70% of these cases are associated with prior tobacco consumption and/or cigarette smoking, suggesting a direct causal relationship. The development and progression of lung cancer and other malignancies involves the loss of genetic stability, resulting in acquisition of cumulative genetic changes; this affords the cell increased malignant potential. As such, an understanding of the mechanisms through which these events may occur will potentially allow for development of new anticancer therapies. This review will address the association between lung cancer and genetic instability, with a central focus on genetic mutations in the DNA damage repair pathways. In addition, we will discuss the potential clinical exploitation of these pathways, both in terms of biomarker staging, as well as through direct therapeutic targeting.

Divest Harvard: Climate justice, higher education, and fossil fuel divestment

On the 19 November 2014, seven Harvard students — the Harvard Climate Justice Coalition — have brought a legal action against Harvard University to compel it to withdraw its investments from fossil fuel companies. The plaintiffs include the Harvard Climate Justice Coalition; Alice Cherry, a law student; Benjamin Franta, a physics student interested in renewable energy; Sidni Frederick, a student of history and literature; Joseph Hamilton, a law student; Olivia Kivel, a biologist interested in sustainable farming; Talia Rothstein, a student of history and literature; and Kelsey Skaggs, a law student from Alaska interested in climate justice. The Harvard Climate Justice Coalition also bringing the lawsuit as ‘next friend of Plaintiffs Future Generations, individuals not yet born or too young to assert their rights but whose future health, safety, and welfare depends on current efforts to slow the pace of climate change.’ The case of Harvard Climate Justice Coalition v. President and Fellows of Harvard College, is being heard in the Suffolk County Superior Court of Massachusetts. The dispute will be an important precedent on the ongoing policy and legal battles in respect of climate change, education, and fossil fuel divestment.

Fossil free Stanford: Universities, climate ethics, and fossil fuel divestment

There has been an international movement led by 350.org, Bill McKibben, and student groups to encourage schools, universities, and educational institutions to divest their endowments of fossil fuel stocks. The decision of Stanford University on coal divestment should an inspiration for elite universities around the world.

The fossil calibration database - A new resource for divergence dating

Fossils provide the principal basis for temporal calibrations, which are critical to the accuracy of divergence dating analyses. Translating fossil data into minimum and maximum bounds for calibrations is the most important, and often least appreciated, step of divergence dating. Properly justified calibrations require the synthesis of phylogenetic, paleontological, and geological evidence and can be difficult for non-specialists to formulate. The dynamic nature of the fossil record (e.g., new discoveries, taxonomic revisions, updates of global or local stratigraphy) requires that calibration data be updated continually lest they become obsolete. Here, we announce the Fossil Calibration Database (http://fossilcalibrations.org), a new open-access resource providing vetted fossil calibrations to the scientific community. Calibrations accessioned into this database are based on individual fossil specimens and follow best practices for phylogenetic justification and geochronological constraint. The associated Fossil Calibration Series, a calibration-themed publication series at Palaeontologia Electronica, will serve as one key pipeline for peer-reviewed calibrations to enter the database.

Four mammal fossil calibrations: Balancing competing palaeontological and molecular considerations

With the introduction of relaxed-clock molecular dating methods, the role of fossil calibration has expanded from providing a timescale, to also informing the models for molecular rate variation across the phylogeny. Here I suggest fossil calibration bounds for four mammal clades, Monotremata (platypus and echidnas), Macropodoidea (kangaroos and potoroos), Caviomorpha-Phiomorpha (South American and African hystricognath rodents), and Chiroptera (bats). In each case I consider sources of uncertainty in the fossil record and provide a molecular dating analysis to examine how the suggested calibration priors are further informed by other mammal fossil calibrations and molecular data.

Future Fund drops tobacco: Should fossil fuels be next?

After a year long public campaign, the Future Fund has today announced plans to end its $222 million investment in tobacco.

Can the Gates Foundation be convinced to dump fossil fuels?

This week, The Guardian newspaper has campaigned for the Bill and Melinda Gates Foundation to divest its fossil fuel investments – which the newspaper claims are worth US$1.4 billion. The foundation can and should address the climate crisis, particularly given the threat it poses to food security, public health, human rights, and the development agenda.

Genomic architecture of ecologically divergent body shape in a pair of sympatric crater lake cichlid fishes

Determining the genetic bases of adaptations and their roles in speciation is a prominent issue in evolutionary biology. Cichlid fish species flocks are a prime example of recent rapid radiations, often associated with adaptive phenotypic divergence from a common ancestor within a short period of time. In several radiations of freshwater fishes, divergence in ecomorphological traits - including body shape, colour, lips and jaws - is thought to underlie their ecological differentiation, specialization and, ultimately, speciation. The Midas cichlid species complex (Amphilophus spp.) of Nicaragua provides one of the few known examples of sympatric speciation where species have rapidly evolved different but parallel morphologies in young crater lakes. This study identified significant QTL for body shape using SNPs generated via ddRAD sequencing and geometric morphometric analyses of a cross between two ecologically and morphologically divergent, sympatric cichlid species endemic to crater Lake Apoyo: an elongated limnetic species (Amphilophus zaliosus) and a high-bodied benthic species (Amphilophus astorquii). A total of 453 genome-wide informative SNPs were identified in 240 F-2 hybrids. These markers were used to construct a genetic map in which 25 linkage groups were resolved. Seventy-two segregating SNPs were linked to 11 QTL. By annotating the two most highly supported QTL-linked genomic regions, genes that might contribute to divergence in body shape along the benthic-limnetic axis in Midas cichlid sympatric adaptive radiations were identified. These results suggest that few genomic regions of large effect contribute to early stage divergence in Midas cichlids.

Respiratory Exacerbations in Indigenous Children From Two Countries With Non-Cystic Fibrosis Chronic Suppurative Lung Disease/Bronchiectasis

BACKGROUND: Acute respiratory exacerbations (AREs) cause morbidity and lung function decline in children with chronic suppurative lung disease (CSLD) and bronchiectasis. In a prospective longitudinal cohort study, we determined the patterns of AREs and factors related to increased risks for AREs in children with CSLD/bronchiectasis. METHODS: Ninety-three indigenous children aged 0.5 to 8 years with CSLD/bronchiectasis in Australia (n = 57) and Alaska (n = 36) during 2004 to 2009 were followed for > 3 years. Standardized parent interviews, physical examinations, and medical record reviews were undertaken at enrollment and every 3 to 6 months thereafter. RESULTS: Ninety-three children experienced 280 AREs (median = 2, range = 0-11 per child) during the 3-year period; 91 (32%) were associated with pneumonia, and 43 (15%) resulted in hospitalization. Of the 93 children, 69 (74%) experienced more than two AREs over the 3-year period, and 28 (30%) had more than one ARE in each study year. The frequency of AREs declined significantly over each year of follow-up. Factors associated with recurrent (two or more) AREs included age < 3 years, ARE-related hospitalization in the first year of life, and pneumonia or hospitalization for ARE in the year preceding enrollment. Factors associated with hospitalizations for AREs in the first year of study included age < 3 years, female caregiver education, and regular use of bronchodilators. CONCLUSIONS: AREs are common in children with CSLD/bronchiectasis, but with clinical care and time AREs occur less frequently. All children with CSLD/bronchiectasis require comprehensive care; however, treatment strategies may differ for these patients based on their changing risks for AREs during each year of care.