Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma.

BACKGROUND: As asthma symptoms worsen, patients typically rely on short-acting ß2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation. METHODS: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide (with each dose consisting of two actuations of 90 µg and 80 µg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 µg of albuterol and 80 µg of budesonide (with each dose consisting of two actuations of 90 µg and 40 µg, respectively [the lower-dose combination group]), or 180 µg of albuterol (with each dose consisting of two actuations of 90 µg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population. RESULTS: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups. CONCLUSIONS: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.).

Labile Carbon from Artificial Roots Alters the Patterns of N2O and N2 Production in Agricultural Soils.

Labile carbon (C) continuously delivered from the rhizosphere profoundly affects terrestrial nitrogen (N) cycling. However, nitrous oxide (N2O) and dinitrogen (N2) production in agricultural soils in the presence of continuous root C exudation with applied N remains poorly understood. We conducted an incubation experiment using artificial roots to continuously deliver small-dose labile C combined with 15N tracers to investigate N2O and N2 emissions in agricultural soils with pH and organic C (SOC) gradients. A significantly negative exponential relationship existed between N2O and N2 emissions under continuous C exudation. Increasing soil pH significantly promoted N2 emissions while reducing N2O emissions. Higher SOC further promoted N2 emissions in alkaline soils. Native soil-N (versus fertilizer-N) was the main source of N2O (average 67%) and N2 (average 80%) emissions across all tested soils. Our study revealed the overlooked high N2 emissions, mainly derived from native soil-N and strengthened by increasing soil pH, under relatively real-world conditions with continuous root C exudation. This highlights the important role of N2O and N2 production from native soil-N in terrestrial N cycling when there is a continuous C supply (e.g., plant-root exudate) and helps mitigate emissions and constrain global budgets of the two concerned nitrogenous gases.

Reducing the environmental impact of rice production in subtropical India by minimising reactive nitrogen loss.

The future of reactive nitrogen (N) for subtropical lowland rice to be characterised under diverse N-management to develop adequate sustainable practices. It is a challenge to increase the efficiency of N use in lowland rice, as N can be lost in various ways, e.g., through nitrous oxide (N2O) or dinitrogen (N2) emissions, ammonia (NH3) volatilization and nitrate (NO3-) leaching. A field study was carried out in the subsequent wet (2021) and dry (2022) seasons to assess the impacts of different N management strategies on yield, N use efficiency and different N losses in a double-cropped rice system. Seven different N-management practices including application of chemical fertilisers, liquid organic fertiliser, nitrification inhibitors, organic nutrient management and integrated nutrient management (INM) were studied. The application of soil test-based neem-coated urea (NCU) during the wet season resulted in the highest economic yield, while integrated nutrient management showed the highest economic yield during the dry season. Total N losses by volatilization of NH3, N2O loss and leaching were 0.06-4.73, 0.32-2.14 and 0.25-1.93 kg ha-1, corresponding to 0.06-5.84%, 0.11-2.20% and 0.09-1.81% of total applied N, respectively. The total N-uptake in grain and straw was highest in INM (87-89% over control) followed by the soil test-based NCU (77-82% over control). In comparison, recovery efficiency of N was maximum from application of NCU + dicyandiamide during both the seasons. The N footprint of paddy rice ranged 0.46-2.01 kg N-eq. t-1 during both seasons under various N management. Ammonia volatilization was the process responsible for the largest N loss, followed by N2O emissions, and NO3- leaching in these subtropical lowland rice fields. After ranking the different N management practices on a scale of 1-7, soil test-based NCU was considered the best N management approach in the wet year 2021, while INM scored the best in the dry year 2022.

Challenges of accounting nitrous oxide emissions from agricultural crop residues.

Crop residues are important inputs of carbon (C) and nitrogen (N) to soils and thus directly and indirectly affect nitrous oxide (N2 O) emissions. As the current inventory methodology considers N inputs by crop residues as the sole determining factor for N2 O emissions, it fails to consider other underlying factors and processes. There is compelling evidence that emissions vary greatly between residues with different biochemical and physical characteristics, with the concentrations of mineralizable N and decomposable C in the residue biomass both enhancing the soil N2 O production potential. High concentrations of these components are associated with immature residues (e.g., cover crops, grass, legumes, and vegetables) as opposed to mature residues (e.g., straw). A more accurate estimation of the short-term (months) effects of the crop residues on N2 O could involve distinguishing mature and immature crop residues with distinctly different emission factors. The medium-term (years) and long-term (decades) effects relate to the effects of residue management on soil N fertility and soil physical and chemical properties, considering that these are affected by local climatic and soil conditions as well as land use and management. More targeted mitigation efforts for N2 O emissions, after addition of crop residues to the soil, are urgently needed and require an improved methodology for emission accounting. This work needs to be underpinned by research to (1) develop and validate N2 O emission factors for mature and immature crop residues, (2) assess emissions from belowground residues of terminated crops, (3) improve activity data on management of different residue types, in particular immature residues, and (4) evaluate long-term effects of residue addition on N2 O emissions.

Using nitrification inhibitors and deep placement to tackle the trade-offs between NH3 and N2 O emissions in global croplands.

Ammonia (NH3 ) and nitrous oxide (N2 O) are two important air pollutants that have major impacts on climate change and biodiversity losses. Agriculture represents their largest source and effective mitigation measures of individual gases have been well studied. However, the interactions and trade-offs between NH3 and N2 O emissions remain uncertain. Here, we report the results of a two-year field experiment in a wheat-maize rotation in the North China Plain (NCP), a global hotspot of reactive N emissions. Our analysis is supported by a literature synthesis of global croplands, to understand the interactions between NH3 and N2 O emissions and to develop the most effective approaches to jointly mitigate NH3 and N2 O emissions. Field results indicated that deep placement of urea with nitrification inhibitors (NIs) reduced both emissions of NH3 by 67% to 90% and N2 O by 73% to 100%, respectively, in comparison with surface broadcast urea which is the common farmers' practice. But, deep placement of urea, surface broadcast urea with NIs, and application of urea with urease inhibitors probably led to trade-offs between the two gases, with a mitigation potential of -201% to 101% for NH3 and -112% to 89% for N2 O. The literature synthesis showed that deep placement of urea with NIs had an emission factor of 1.53%-4.02% for NH3 and 0.22%-0.36% for N2 O, which were much lower than other fertilization regimes and the default values recommended by IPCC guidelines. This would translate to a reduction of 3.86-5.47 Tg N yr-1 of NH3 and 0.41-0.50 Tg N yr-1 of N2 O emissions, respectively, when adopting deep placement of urea with NIs (relative to current practice) in global croplands. We conclude that the combination of NIs and deep placement of urea can successfully tackle the trade-offs between NH3 and N2 O emissions, therefore avoiding N pollution swapping in global croplands.

Effects of pharmaceuticals on the nitrogen cycle in water and soil: a review.

The effects of pharmaceuticals on the nitrogen cycle in water and soil have recently become an increasingly important issue for environmental research. However, a few studies have investigated the direct effects of pharmaceuticals on the nitrogen cycle in water and soil. Pharmaceuticals can contribute to inhibition and stimulation of nitrogen cycle processes in the environment. Some pharmaceuticals have no observable effect on the nitrogen cycle in water and soil while others appeared to inhibit or stimulate for it. This review reports on the most recent evidence of effects of pharmaceuticals on the nitrogen cycle processes by examination of the potential impact of pharmaceuticals on nitrogen fixation, nitrification, ammonification, denitrification, and anammox. Research studies have identified pharmaceuticals that can either inhibit or stimulate nitrification, ammonification, denitrification, and anammox. Among these, amoxicillin, chlortetracycline, ciprofloxacin, clarithromycin, enrofloxacin, erythromycin, narasin, norfloxacin, and sulfamethazine had the most significant effects on nitrogen cycle processes. This review also clearly demonstrates that some nitrogen transformation processes such as nitrification show much higher sensitivity to the presence of pharmaceuticals than other nitrogen transformations or flows such as mineralization or ammonia volatilization. We conclude by suggesting that future studies take a more comprehensive approach to report on pharmaceuticals' impact on the nitrogen cycle process.

Characterising the biophysical, economic and social impacts of soil carbon sequestration as a greenhouse gas removal technology.

To limit warming to well below 2°C, most scenario projections rely on greenhouse gas removal technologies (GGRTs); one such GGRT uses soil carbon sequestration (SCS) in agricultural land. In addition to their role in mitigating climate change, SCS practices play a role in delivering agroecosystem resilience, climate change adaptability and food security. Environmental heterogeneity and differences in agricultural practices challenge the practical implementation of SCS, and our analysis addresses the associated knowledge gap. Previous assessments have focused on global potentials, but there is a need among policymakers to operationalise SCS. Here, we assess a range of practices already proposed to deliver SCS, and distil these into a subset of specific measures. We provide a multidisciplinary summary of the barriers and potential incentives towards practical implementation of these measures. First, we identify specific practices with potential for both a positive impact on SCS at farm level and an uptake rate compatible with global impact. These focus on: (a) optimising crop primary productivity (e.g. nutrient optimisation, pH management, irrigation); (b) reducing soil disturbance and managing soil physical properties (e.g. improved rotations, minimum till); (c) minimising deliberate removal of C or lateral transport via erosion processes (e.g. support measures, bare fallow reduction); (d) addition of C produced outside the system (e.g. organic manure amendments, biochar addition); (e) provision of additional C inputs within the cropping system (e.g. agroforestry, cover cropping). We then consider economic and non-cost barriers and incentives for land managers implementing these measures, along with the potential externalised impacts of implementation. This offers a framework and reference point for holistic assessment of the impacts of SCS. Finally, we summarise and discuss the ability of extant scientific approaches to quantify the technical potential and externalities of SCS measures, and the barriers and incentives to their implementation in global agricultural systems.

COMP Report: A survey of radiation safety regulations for medical imaging x-ray equipment in Canada.

X-ray regulations and room design methodology vary widely across Canada. The Canadian Organization of Medical Physicists (COMP) conducted a survey in 2016/2017 to provide a useful snapshot of existing variations in rules and methodologies for human patient medical imaging facilities. Some jurisdictions no longer have radiation safety regulatory requirements and COMP is concerned that lack of regulatory oversight might erode safe practices. Harmonized standards will facilitate oversight that will ensure continued attention is given to public safety and to control workplace exposure. COMP encourages all Canadian jurisdictions to adopt the dose limits and constraints outlined in Health Canada Safety Code 35 with the codicil that the design standards be updated to those outlined in NCRP 147 and BIR 2012.

A critical review of the impacts of cover crops on nitrogen leaching, net greenhouse gas balance and crop productivity.

Cover crops play an increasingly important role in improving soil quality, reducing agricultural inputs and improving environmental sustainability. The main objectives of this critical global review and systematic analysis were to assess cover crop practices in the context of their impacts on nitrogen leaching, net greenhouse gas balances (NGHGB) and crop productivity. Only studies that investigated the impacts of cover crops and measured one or a combination of nitrogen leaching, soil organic carbon (SOC), nitrous oxide (N2 O), grain yield and nitrogen in grain of primary crop, and had a control treatment were included in the analysis. Long-term studies were uncommon, with most data coming from studies lasting 2-3 years. The literature search resulted in 106 studies carried out at 372 sites and covering different countries, climatic zones and management. Our analysis demonstrates that cover crops significantly (p < 0.001) decreased N leaching and significantly (p < 0.001) increased SOC sequestration without having significant (p > 0.05) effects on direct N2 O emissions. Cover crops could mitigate the NGHGB by 2.06 ± 2.10 Mg CO2 -eq ha-1  year-1 . One of the potential disadvantages of cover crops identified was the reduction in grain yield of the primary crop by ≈4%, compared to the control treatment. This drawback could be avoided by selecting mixed cover crops with a range of legumes and non-legumes, which increased the yield by ≈13%. These advantages of cover crops justify their widespread adoption. However, management practices in relation to cover crops will need to be adapted to specific soil, management and regional climatic conditions.

Weakened growth of cropland-N2 O emissions in China associated with nationwide policy interventions.

China has experienced rapid agricultural development over recent decades, accompanied by increased fertilizer consumption in croplands; yet, the trend and drivers of the associated nitrous oxide (N2 O) emissions remain uncertain. The primary sources of this uncertainty are the coarse spatial variation of activity data and the incomplete model representation of N2 O emissions in response to agricultural management. Here, we provide new data-driven estimates of cropland-N2 O emissions across China in 1990-2014, compiled using a global cropland-N2 O flux observation dataset, nationwide survey-based reconstruction of N-fertilization and irrigation, and an updated nonlinear model. In addition, we have evaluated the drivers behind changing cropland-N2 O patterns using an index decomposition analysis approach. We find that China's annual cropland-N2 O emissions increased on average by 11.2 Gg N/year2 (p < .001) from 1990 to 2003, after which emissions plateaued until 2014 (2.8 Gg N/year2 , p = .02), consistent with the output from an ensemble of process-based terrestrial biosphere models. The slowdown of the increase in cropland-N2 O emissions after 2003 was pervasive across two thirds of China's sowing areas. This change was mainly driven by the nationwide reduction in N-fertilizer applied per area, partially due to the prevalence of nationwide technological adoptions. This reduction has almost offset the N2 O emissions induced by policy-driven expansion of sowing areas, particularly in the Northeast Plain and the lower Yangtze River Basin. Our results underline the importance of high-resolution activity data and adoption of nonlinear model of N2 O emission for capturing cropland-N2 O emission changes. Improving the representation of policy interventions is also recommended for future projections.

Computational Modeling and Simulation of CO2 Capture by Aqueous Amines.

We review the literature on the use of computational methods to study the reactions between carbon dioxide and aqueous organic amines used to capture CO2 prior to storage, reuse, or sequestration. The focus is largely on the use of high level quantum chemical methods to study these reactions, although the review also summarizes research employing hybrid quantum mechanics/molecular mechanics methods and molecular dynamics. We critically review the effects of basis set size, quantum chemical method, solvent models, and other factors on the accuracy of calculations to provide guidance on the most appropriate methods, the expected performance, method limitations, and future needs and trends. The review also discusses experimental studies of amine-CO2 equilibria, kinetics, measurement and prediction of amine pKa values, and degradation reactions of aqueous organic amines. Computational simulations of carbon capture reaction mechanisms are also comprehensively described, and the relative merits of the zwitterion, termolecular, carbamic acid, and bicarbonate mechanisms are discussed in the context of computational and experimental studies. Computational methods will become an increasingly valuable and complementary adjunct to experiments for understanding mechanisms of amine-CO2 reactions and in the design of more efficient carbon capture agents with acceptable cost and toxicities.

Oxygen Regulates Nitrous Oxide Production Directly in Agricultural Soils.

Oxygen (O2) plays a critical and yet poorly understood role in regulating nitrous oxide (N2O) production in well-structured agricultural soils. We investigated the effects of in situ O2 dynamics on N2O production in a typical intensively managed Chinese cropping system under a range of environmental conditions (temperature, moisture, ammonium, nitrate, dissolved organic carbon, and so forth). Climate and management (fertilization, irrigation, precipitation, and temperature), and their interactions significantly affected soil O2 and N2O concentrations (P < 0.05). Soil O2 concentration was the most significant factor correlating with soil N2O concentration (r = -0.71) when compared with temperature, water-filled pore space, and ammonium concentration (r = 0.30, 0.25, and 0.26, respectively). Soil N2O concentration increased exponentially with decreasing soil O2 concentrations. The exponential model of N treatments and fertilization with irrigation/precipitation events predicted 74-90% and 58% of the variance in soil N2O concentrations, respectively. Our results highlight that the soil O2 status is the proximal, direct, and the most decisive environmental trigger for N2O production, outweighing the effects of other factors and could be a key variable integrating the aggregated effects of various complex interacting variables. This study offers new opportunities for developing more sensitive approaches to predicting and through appropriate management interventions mitigating N2O emissions from agricultural soils.

Chinese cropping systems are a net source of greenhouse gases despite soil carbon sequestration.

Soil carbon sequestration is being considered as a potential pathway to mitigate climate change. Cropland soils could provide a sink for carbon that can be modified by farming practices; however, they can also act as a source of greenhouse gases (GHG), including not only nitrous oxide (N2 O) and methane (CH4 ), but also the upstream carbon dioxide (CO2 ) emissions associated with agronomic management. These latter emissions are also sometimes termed "hidden" or "embedded" CO2 . In this paper, we estimated the net GHG balance for Chinese cropping systems by considering the balance of soil carbon sequestration, N2 O and CH4 emissions, and the upstream CO2 emissions of agronomic management from a life cycle perspective during 2000-2017. Results showed that although soil organic carbon (SOC) increased by 23.2 ± 8.6 Tg C per year, the soil N2 O and CH4 emissions plus upstream CO2 emissions arising from agronomic management added 269.5 ± 21.1 Tg C-eq per year to the atmosphere. These findings demonstrate that Chinese cropping systems are a net source of GHG emissions and that total GHG emissions are about 12 times larger than carbon uptake by soil sequestration. There were large variations between different cropping systems in the net GHG balance ranging from 328 to 7,567 kg C-eq ha-1  year-1 , but all systems act as a net GHG source to the atmosphere. The main sources of total GHG emissions are nitrogen fertilization (emissions during production and application), power use for irrigation, and soil N2 O and CH4 emissions. Optimizing agronomic management practices, especially fertilization, irrigation, plastic mulching, and crop residues to reduce total GHG emissions from the whole chain is urgently required in order to develop a low-carbon future for Chinese crop production.

Nitrous Oxide Emissions Increase Exponentially When Optimum Nitrogen Fertilizer Rates Are Exceeded in the North China Plain.

The IPCC assume a linear relationship between nitrogen (N) application rate and nitrous oxide (N2O) emissions in inventory reporting, however, a growing number of studies show a nonlinear relationship under specific soil-climatic conditions. In the North China plain, a global hotspot of N2O emissions, covering a land as large as Germany, the correlation between N rate and N2O emissions remains unclear. We have therefore specifically investigated the N2O response to N applications by conducting field experiments with five N rates, and high-frequency measurements of N2O emissions across contrasting climatic years. Our results showed that cumulative and yield-scaled N2O emissions both increased exponentially as N applications were raised above the optimum rate in maize ( Zea mays L.). In wheat ( Triticum aestivum L.) there was a corresponding quadratic increase in N2O emissions with the magnitude of the response in 2012-2013 distinctly larger than that in 2013-2014 owing to the effects of extreme snowfall. Existing empirical models (including the IPCC approach) of the N2O response to N rate have overestimated N2O emissions in the North China plain, even at high N rates. Our study therefore provides a new and robust analysis of the effects of fertilizer rate and climatic conditions on N2O emissions.

SPAG5 as a prognostic biomarker and chemotherapy sensitivity predictor in breast cancer: a retrospective, integrated genomic, transcriptomic, and protein analysis.

BACKGROUND: Proliferation markers and profiles have been recommended for guiding the choice of systemic treatments for breast cancer. However, the best molecular marker or test to use has not yet been identified. We did this study to identify factors that drive proliferation and its associated features in breast cancer and assess their association with clinical outcomes and response to chemotherapy. METHODS: We applied an artificial neural network-based integrative data mining approach to data from three cohorts of patients with breast cancer (the Nottingham discovery cohort (n=171), Uppsala cohort (n=249), and Molecular Taxonomy of Breast Cancer International Consortium [METABRIC] cohort; n=1980). We then identified the genes with the most effect on other genes in the resulting interactome map. Sperm-associated antigen 5 (SPAG5) featured prominently in our interactome map of proliferation and we chose to take it forward in our analysis on the basis of its fundamental role in the function and dynamic regulation of mitotic spindles, mitotic progression, and chromosome segregation fidelity. We investigated the clinicopathological relevance of SPAG5 gene copy number aberrations, mRNA transcript expression, and protein expression and analysed the associations of SPAG5 copy number aberrations, transcript expression, and protein expression with breast cancer-specific survival, disease-free survival, distant relapse-free survival, pathological complete response, and residual cancer burden in the Nottingham discovery cohort, Uppsala cohort, METABRIC cohort, a pooled untreated lymph node-negative cohort (n=684), a multicentre combined cohort (n=5439), the Nottingham historical early stage breast cancer cohort (Nottingham-HES; n=1650), Nottingham early stage oestrogen receptor-negative breast cancer adjuvant chemotherapy cohort (Nottingham-oestrogen receptor-negative-ACT; n=697), the Nottingham anthracycline neoadjuvant chemotherapy cohort (Nottingham-NeoACT; n=200), the MD Anderson taxane plus anthracycline-based neoadjuvant chemotherapy cohort (MD Anderson-NeoACT; n=508), and the multicentre phase 2 neoadjuvant clinical trial cohort (phase 2 NeoACT; NCT00455533; n=253). FINDINGS: In the METABRIC cohort, we detected SPAG5 gene gain or amplification at the Ch17q11.2 locus in 206 (10%) of 1980 patients overall, 46 (19%) of 237 patients with a PAM50-HER2 phenotype, and 87 (18%) of 488 patients with PAM50-LumB phenotype. Copy number aberration leading to SPAG5 gain or amplification and high SPAG5 transcript and SPAG5 protein concentrations were associated with shorter overall breast cancer-specific survival (METABRIC cohort [copy number aberration]: hazard ratio [HR] 1·50, 95% CI 1·18-1·92, p=0·00010; METABRIC cohort [transcript]: 1·68, 1·40-2·01, p<0·0001; and Nottingham-HES-breast cancer cohort [protein]: 1·68, 1·32-2·12, p<0·0001). In multivariable analysis, high SPAG5 transcript and SPAG5 protein expression were associated with reduced breast cancer-specific survival at 10 years compared with lower concentrations (Uppsala: HR 1·62, 95% CI 1·03-2·53, p=0·036; METABRIC: 1·27, 1·02-1·58, p=0·034; untreated lymph node-negative cohort: 2·34, 1·24-4·42, p=0·0090; and Nottingham-HES: 1·73, 1·23-2·46, p=0·0020). In patients with oestrogen receptor-negative breast cancer with high SPAG5 protein expression, anthracycline-based adjuvant chemotherapy increased breast cancer-specific survival overall compared with that for patients who did not receive chemotherapy (Nottingham-oestrogen receptor-negative-ACT cohort: HR 0·37, 95% CI 0·20-0·60, p=0·0010). Multivariable analysis showed high SPAG5 transcript concentrations to be independently associated with longer distant relapse-free survival after receiving taxane plus anthracycline neoadjuvant chemotherapy (MD Anderson-NeoACT: HR 0·68, 95% CI 0·48-0·97, p=0·031). In multivariable analysis, both high SPAG5 transcript and high SPAG5 protein concentrations were independent predictors for a higher proportion of patients achieving a pathological complete response after combination cytotoxic chemotherapy (MD Anderson-NeoACT: OR 1·71, 95% CI, 1·07-2·74, p=0·024; Nottingham-ACT: 8·75, 2·42-31·62, p=0·0010). INTERPRETATION: SPAG5 is a novel amplified gene on Ch17q11.2 in breast cancer. The transcript and protein products of SPAG5 are independent prognostic and predictive biomarkers that might have clinical utility as biomarkers for combination cytotoxic chemotherapy sensitivity, especially in oestrogen receptor-negative breast cancer. FUNDING: Nottingham Hospitals Charity and the John and Lucille van Geest Foundation.

KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach.

BACKGROUND: There remains a need to identify and validate biomarkers for predicting prostate cancer (CaP) outcomes using robust and routinely available pathology techniques to identify men at most risk of premature death due to prostate cancer. Previous immunohistochemical studies suggest the proliferation marker Ki67 might be a predictor of survival, independently of PSA and Gleason score. We performed a validation study of Ki67 as a marker of survival and disease progression and compared its performance against another candidate biomarker, DLX2, selected using artificial neural network analysis. METHODS: A tissue microarray (TMA) was constructed from transurethral resected prostatectomy histology samples (n=192). Artificial neural network analysis was used to identify candidate markers conferring increased risk of death and metastasis in a public cDNA array. Immunohistochemical analysis of the TMA was carried out and univariate and multivariate tests performed to explore the association of tumour protein levels of Ki67 and DLX2 with time to death and metastasis. RESULTS: Univariate analysis demonstrated Ki67 as predictive of CaP-specific survival (DSS; P=0.022), and both Ki67 (P=0.025) and DLX2 (P=0.001) as predictive of future metastases. Multivariate analysis demonstrated Ki67 as independent of PSA, Gleason score and D'Amico risk category for DSS (HR=2.436, P=0.029) and both Ki67 (HR=3.296, P=0.023) and DLX2 (HR=3.051, P=0.003) as independent for future metastases. CONCLUSIONS: High Ki67 expression is only present in 6.8% of CaP patients and is predictive of reduced survival and increased risk of metastasis, independent of PSA, Gleason score and D'Amico risk category. DLX2 is a novel marker of increased metastasis risk found in 73% patients and 8.2% showed co-expression with a high Ki67 score. Two cancer cell proliferation markers, Ki67 and DLX2, may be able to inform clinical decision-making when identifying patients for active surveillance.

How Dirhodium Catalyst Controls the Enantioselectivity of [3 + 2]-Cycloaddition between Nitrone and Vinyldiazoacetate: A Density Functional Theory Study.

The origin of enantioselectivity in the dirhodium-catalyzed [3 + 2]-cycloaddition of nitrone and vinyldiazoacetate has been investigated using dispersion-corrected density functional theory. Taking a more realistic account of bulky ligands in models of the dirhodium catalyst when investigating its catalytic behavior is crucial for describing the effects resulting from a high level of asymmetric induction. More than one active site can be located and the extra reactivity is provided by an electron-donation interaction between the substrate and an additional Rh2L4 catalyst.

Novel prostate acid phosphatase-based peptide vaccination strategy induces antigen-specific T-cell responses and limits tumour growth in mice.

Treatment options for patients with advanced prostate cancer remain limited and rarely curative. Prostatic acid phosphatase (PAP) is a prostate-specific protein overexpressed in 95% of prostate tumours. An FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE® (sipuleucel-T), has been shown to prolong survival, however the precise sequence of the PAP protein responsible for the outcome is unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, preclinical studies using PAP have the potential to be directly relevant to clinical setting. Here, we show three PAP epitopes naturally processed and presented in the context of HHDII/DR1 (114-128, 299-313, and 230-244). The PAP-114-128 epitope elicits CD4(+) and CD8(+) T-cell-specific responses in C57BL/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody®), PAP-114-128 prevents and reduces the growth of transgenic adenocarcinoma of mouse prostate-C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect is associated with infiltration of CD8(+) tumour-infiltrating lymphocytes and the generation of high avidity T cells secreting elevated levels of IFN-γ. PAP-114-128 therefore appears to be a highly relevant peptide on which to base vaccines for the treatment of prostate cancer.

Susceptibility of Adult Cat Fleas (Siphonaptera: Pulicidae) to Insecticides and Status of Insecticide Resistance Mutations at the Rdl and Knockdown Resistance Loci.

The susceptibility of 12 field-collected isolates and 4 laboratory strains of cat fleas, Ctenocephalides felis was determined by topical application of some of the insecticides used as on-animal therapies to control them. In the tested field-collected flea isolates the LD50 values for fipronil and imidacloprid ranged from 0.09 to 0.35 ng/flea and 0.02 to 0.19 ng/flea, respectively, and were consistent with baseline figures published previously. The extent of variation in response to four pyrethroid insecticides differed between compounds with the LD50 values for deltamethrin ranging from 2.3 to 28.2 ng/flea, etofenprox ranging from 26.7 to 86.7 ng/flea, permethrin ranging from 17.5 to 85.6 ng/flea, and d-phenothrin ranging from 14.5 to 130 ng/flea. A comparison with earlier data for permethrin and deltamethrin implied a level of pyrethroid resistance in all isolates and strains. LD50 values for tetrachlorvinphos ranged from 20.0 to 420.0 ng/flea. The rdl mutation (conferring target-site resistance to cyclodiene insecticides) was present in most field-collected and laboratory strains, but had no discernible effect on responses to fipronil, which acts on the same receptor protein as cyclodienes. The kdr and skdr mutations conferring target-site resistance to pyrethroids but segregated in opposition to one another, precluding the formation of genotypes homozygous for both mutations.