SRF617 Is a Potent Inhibitor of CD39 with Immunomodulatory and Antitumor Properties.

CD39 (ENTPD1) is a key enzyme responsible for degradation of extracellular ATP and is upregulated in the tumor microenvironment (TME). Extracellular ATP accumulates in the TME from tissue damage and immunogenic cell death, potentially initiating proinflammatory responses that are reduced by the enzymatic activity of CD39. Degradation of ATP by CD39 and other ectonucleotidases (e.g., CD73) results in extracellular adenosine accumulation, constituting an important mechanism for tumor immune escape, angiogenesis induction, and metastasis. Thus, inhibiting CD39 enzymatic activity can inhibit tumor growth by converting a suppressive TME to a proinflammatory environment. SRF617 is an investigational, anti-CD39, fully human IgG4 Ab that binds to human CD39 with nanomolar affinity and potently inhibits its ATPase activity. In vitro functional assays using primary human immune cells demonstrate that inhibiting CD39 enhances T-cell proliferation, dendritic cell maturation/activation, and release of IL-1ß and IL-18 from macrophages. In vivo, SRF617 has significant single-agent antitumor activity in human cell line-derived xenograft models that express CD39. Pharmacodynamic studies demonstrate that target engagement of CD39 by SRF617 in the TME inhibits ATPase activity, inducing proinflammatory mechanistic changes in tumor-infiltrating leukocytes. Syngeneic tumor studies using human CD39 knock-in mice show that SRF617 can modulate CD39 levels on immune cells in vivo and can penetrate the TME of an orthotopic tumor, leading to increased CD8+ T-cell infiltration. Targeting CD39 is an attractive approach for treating cancer, and, as such, the properties of SRF617 make it an excellent drug development candidate.

Age influences the thermal suitability of Plasmodium falciparum transmission in the Asian malaria vector Anopheles stephensi.

Models predicting disease transmission are vital tools for long-term planning of malaria reduction efforts, particularly for mitigating impacts of climate change. We compared temperature-dependent malaria transmission models when mosquito life-history traits were estimated from a truncated portion of the lifespan (a common practice) versus traits measured across the full lifespan. We conducted an experiment on adult female Anopheles stephensi, the Asian urban malaria mosquito, to generate daily per capita values for mortality, egg production and biting rate at six constant temperatures. Both temperature and age significantly affected trait values. Further, we found quantitative and qualitative differences between temperature-trait relationships estimated from truncated data versus observed lifetime values. Incorporating these temperature-trait relationships into an expression governing the thermal suitability of transmission, relative R0(T), resulted in minor differences in the breadth of suitable temperatures for Plasmodium falciparum transmission between the two models constructed from only An. stephensi trait data. However, we found a substantial increase in thermal niche breadth compared with a previously published model consisting of trait data from multiple Anopheles mosquito species. Overall, this work highlights the importance of considering how mosquito trait values vary with mosquito age and mosquito species when generating temperature-based suitability predictions of transmission.

Exudative cloacitis in the kakapo (Strigops habroptilus) potentially linked to Escherichia coli infection.

AIM: To investigate the initiating causes of cloacitis (inflammation of the cloaca) in kakapo (Strigops habroptilus). METHODS: Metagenomics using unbiased RNA or DNA sequencing was applied to faecal material from an 11-year-old female kakapo with exudative cloacitis, and a pool of eight birds (male and female aged 1-20 years) with no current signs or history of the disease. Faecal material from the diseased bird was collected pre- and post-treatment. For RNA sequencing, extracted RNA/DNA was subject to DNase, and the remaining RNA reverse transcribed to cDNA and subject to multiple displacement amplification prior to sequencing. RESULTS: No significant alignment to any known avian virus sequence was obtained from any faecal samples. However significant BLAST alignments to five bacteriophages known to infect enterobacteria were obtained. Strong evidence was obtained for the presence of the bacteriophage Escherichia phage TL-2011b, a bacteriophage known to occur in Escherichia coli causing outbreaks of foodborne disease in humans, in the sample from the diseased bird, but not the non-diseased pool. Differences in E. coli community structure between the diseased bird and the non-diseased pool were also apparent. CONCLUSIONS: Escherichia coli infection of human origin is suggested as a possible cause of exudative cloacitis, although confirmatory work is required to test this hypothesis.

Quantitative proteomics of delirium cerebrospinal fluid.

Delirium is a common cause and complication of hospitalization in older people, being associated with higher risk of future dementia and progression of existing dementia. However relatively little data are available on which biochemical pathways are dysregulated in the brain during delirium episodes, whether there are protein expression changes common among delirium subjects and whether there are any changes which correlate with the severity of delirium. We now present the first proteomic analysis of delirium cerebrospinal fluid (CSF), and one of few studies exploring protein expression changes in delirium. More than 270 proteins were identified in two delirium cohorts, 16 of which were dysregulated in at least 8 of 17 delirium subjects compared with a mild Alzheimer's disease neurological control group, and 31 proteins were significantly correlated with cognitive scores (mini-mental state exam and acute physiology and chronic health evaluation III). Bioinformatics analyses revealed expression changes in several protein family groups, including apolipoproteins, secretogranins/chromogranins, clotting/fibrinolysis factors, serine protease inhibitors and acute-phase response elements. These data not only provide confirmatory evidence that the inflammatory response is a component of delirium, but also reveal dysregulation of protein expression in a number of novel and unexpected clusters of proteins, in particular the granins. Another surprising outcome of this work is the level of similarity of CSF protein profiles in delirium patients, given the diversity of causes of this syndrome. These data provide additional elements for consideration in the pathophysiology of delirium as well as potential biomarker candidates for delirium diagnosis.

Contribution of the second stage of labour to pelvic floor dysfunction: a prospective cohort comparison of nulliparous women.

OBJECTIVE: Maternal expulsive efforts are thought to damage the pelvic floor. We aimed to compare pelvic floor function and anatomy between women who delivered vaginally (VB) versus those with caesarean delivery (CD) prior to the second stage of labour. DESIGN: Prospective cohort. SETTING: University Hospital Midwifery practice. POPULATION: Nulliparas. METHODS: Pregnant nulliparas were recruited during pregnancy and women who underwent CD prior to the 2nd stage of labour at birth were recruited immediately postpartum. Both groups were followed prospectively to 6 months postpartum. MAIN OUTCOME MEASURES: POPQ, perineal ultrasound (U/S) and Paper Towel Test (PTT), an objective measure of stress incontinence; Incontinence Severity Index (ISI), Pelvic Floor Impact Questionnaire (PFIQ-7), Wexner Fecal Incontinence Scale (W) and Female Sexual Function Index (FSFI). RESULTS: 336/448 (75%) VB and 138/224 (62%) CD followed up. The VB group was younger (23.9 ± 4.9 versus 26.6 ± 6.1 years, P < 0.001) and less overweight/obese (38 versus 56%, P < 0.001); baseline functional measures were similar (all P > 0.05). At follow-up, urinary incontinence (UI) (55 versus 46% ISI > 0, P = 0.10), fecal incontinence (FI) (8 versus 13% FI on W, P = 0.12), sexual activity rates (88 versus 92%, P = 0.18) and PFIQ-seven scores were similar. Positive PTT tests (17 versus 6%, P = 0.002) and ≥ Stage 2 prolapse (22 versus 15%, P = 0.03) were higher with VB; differences were limited to points Aa and Ba. U/S findings were not different between groups. Stepwise multivariate analyses controlling for age, body mass index, and non-Hispanic White race for prolapse of points Aa and Ba did not alter conclusions (all P < 0.004). CONCLUSIONS: VB resulted in prolapse changes and objective UI but not in increased self-report pelvic floor dysfunction at 6 months postpartum compared with women who delivered by CD prior to the second stage of labour. The second stage of labour had a modest effect on postpartum pelvic floor function.

Accurate modeling of single-particle cryo-EM images quantitates the benefits expected from using Zernike phase contrast.

The use of a Zernike-type phase plate in biologic cryo-electron microscopy allows the imaging, without using defocus, of what are predominantly phase objects. It is thought that such phase-plate implementations might result in higher quality images, free from the problems of CTF correction that occur when images must be recorded at extremely high values of defocus. In single-particle cryo-electron microscopy it is hoped that these improvements in image quality will facilitate work on structures that have proved difficult to study, either because of their relatively small size or because the structures are not completely homogeneous. There is still a need, however, to quantitate how much improvement can be gained by using a phase plate for single-particle cryo-electron microscopy. We present a method for quantitatively modeling the images recorded with 200keV electrons, for single particles embedded in vitreous ice. We then investigate what difference the use of a phase-plate device could have on the processing of single-particle data. We confirm that using a phase plate results in single-particle datasets in which smaller molecules can be detected, particles can be more accurately aligned and problems of heterogeneity can be more easily addressed.

Genotyping assay for the identification of 2009-2010 pandemic and seasonal H1N1 influenza virus reassortants.

New Zealand identified its first pandemic H1N1 influenza cases in late April 2009, immediately prior to the historical start of the New Zealand influenza season. Both pandemic and oseltamivir-resistant seasonal H1N1 viruses cocirculated in the population for a period of time. Thus, concerns were raised about the possibility of reassortment events between the two strains. An RT-PCR-based genotyping assay was developed so that H1N1 influenza coinfections and reassortants could be detected quickly. The assay differentiated effectively the seasonal and pandemic strains. It also confirmed the identification of the first reported coinfection of pandemic and seasonal H1N1 strains during the 2009 Southern Hemisphere influenza season in New Zealand.

Pandemic influenza A(H1N1)v viruses currently circulating in New Zealand are sensitive to oseltamivir.

New Zealand, like other southern hemisphere countries with a temperate climate, has been in the winter period with seasonal influenza activity. New Zealand has also experienced a dramatic increase in the number of cases of pandemic influenza A(H1N1)v virus. Early reports from the northern hemisphere at the beginning of the pandemic showed that the virus was sensitive to the antiviral drug oseltamivir. In this study we report that pandemic influenza A(H1N1)v viruses currently circulating in New Zealand are sensitive to oseltamivir, but seasonal influenza A(H1N1) viruses - the co-circulating predominant seasonal strain, is resistant to oseltamivir.

Fuzzy-logic modeling of land suitability for hybrid poplar across the Prairie Provinces of Canada.

Determining the feasibility of a large-scale afforestation program is one approach being investigated by the Government of Canada to increase Canada's potential to sequester carbon from the atmosphere. Large-scale afforestation, however, requires knowledge of where it is suitable to establish and grow trees. Spatial models based on Boolean logic and/or statistical models within a geographic information system may be used for this purpose, but empirical environmental data are often lacking, and the association of these data to land suitability is most often a subjective process. As a solution to this problem, this paper presents a fuzzy-logic modeling approach to assess land suitability for afforestation of hybrid poplar (Populus spp.) over the Prairie Provinces of Canada. Expert knowledge regarding the selection and magnitudes of environmental variables were integrated into fuzzy rule sets from which estimates of land suitability were generated and presented in map form. The environmental variables selected included growing season precipitation, climate moisture index, growing degree days, and Canada Land Inventory capability for agriculture and elevation. Approximately 150,000 km2, or 28% of the eligible land base within the Prairie Provinces was found to be suitable for afforestation. Accuracy assessments conducted with fuzzy accuracy methods provided a more descriptive assessment of the resulting land suitability map than figures generated from a more conventional Boolean-based accuracy measure. Modeling, mapping and accuracy assessment issues were identified for future extension of this work to map hybrid poplar land suitability over Canada.

A QTL study of growth and body shape in the inter-species hybrid of Père David's deer (Elaphurus davidianus) and red deer (Cervus elaphus).

An interspecies deer hybrid resource population developed from a cross of Père David's and red deer was used to detect QTL that account for species differences. A genome scan, coupled with composite interval mapping, was conducted to search for QTL controlling body measurements at pre-pubescent age (6 months of age) and puberty (15 months of age) in this interspecies hybrid. Five linkage groups that harbour QTL affecting morphology were identified. A joint-traits analysis was used to search for putative pleiotropic QTL on four of these linkage groups, and three were significantly associated with pleiotropic QTL for nose width and foot length (metacarpal and phalanges), which collectively accounted for 29-58% of the phenotypic difference between the two deer species. This study suggests that a few loci with large pleiotropic effects may be responsible for species-specific differences in growth and structure-related traits.

The Coronary Artery Revascularisation in Diabetes (CARDia) trial: background, aims, and design.

BACKGROUND: Patients with diabetes have an increased incidence and severity of ischemic heart disease, which leads to an increased requirement for coronary revascularization. Comparative information regarding mode of revascularization--coronary artery bypass graft surgery surgery (CABG) or percutaneous coronary intervention (PCI)--is limited, mainly confined to a subanalysis of the Bypass Angioplasty Revascularization (BARI) trial, suggesting a mortality benefit of CABG over PCI. No prospective trial has specifically compared these modes of revascularization in patients with diabetes. OBJECTIVE: The Coronary Artery Revascularisation in Diabetes (CARDia) trial is designed to address the hypothesis that optimal PCI is not inferior to modern CABG as a revascularization strategy for diabetics with multivessel or complex single-vessel coronary disease. The primary end point is a composite of death, nonfatal myocardial infarction, and cerebrovascular accident at 1 year. METHOD: A total of 600 patients with diabetes are to be randomized to either PCI or CABG, with few protocol restrictions on operative techniques or use of new technology. This gives a power of 80% to detect non-inferiority of PCI assuming that the PCI 1-year event rate is 9%. A cardiac surgeon and a cardiologist must agree that a patient is suitable for revascularization by either technique prior to recruitment into the study. Twenty-one centers in the United Kingdom and Ireland are recruiting patients. Data on cost effectiveness, quality of life, and neurocognitive function are being collected. Long-term (3-5 year) follow-up data will also be collected.

A prospective study of long term prognosis in young myocardial infarction survivors: the prognostic value of angiography and exercise testing.

OBJECTIVES: To define the ability of early exercise testing and coronary angiography to predict prognosis in young survivors of myocardial infarction (MI). METHODS: 255 consecutive patients (210 men) aged 55 years or less (mean 48 years) admitted to hospital (1981-85) were eligible. Of these, 150 patients (130 men) who were able to exercise early after MI and underwent coronary angiography within six months constituted the study group and were followed up for up to 15 years. Survival data up to 18 years was obtained for the whole cohort. RESULTS: Survival at a median of 16 years was 52% for the whole cohort, 62% for the study group, and 48% for the excluded group. From nine years onwards survival deteriorated significantly in the study group compared with an age matched background population. Fifteen years after MI, 121 patients (81%) in the study group had had at least one event (death, MI, revascularisation, cardiac readmission, stroke) leaving 29 (19%) event-free. The number of diseased vessels was the major determinant of time to first event (p = 0.001) and event-free survival (p = 0.04). Exercise duration was also important in the prediction of time to first event (p = 0.003). Death was influenced by a history of prior MI. CONCLUSION: The favourable initial survival was followed by significant deterioration after nine years. This late attrition is an important treatment target. Furthermore, this study supports risk stratification early after MI combining angiography with non-invasive tools.

How shared are age-related influences on cognitive and noncognitive variables?

Several theories have suggested that age-related declines in cognitive processing are due to a pervasive unitary mechanism, such as a decline in processing speed. Structural equation model tests have shown some support for such common factor explanations. These results, however, may not be as conclusive as previously claimed. A further analysis of 4 cross-sectional data sets described in Salthouse, Hambrick, and McGuthry (1998) and Salthouse and Czaja (2000) found that although the best fitting model included a common factor in 3 of the data sets, additional direct age paths were significant, indicating the presence of specific age effects. For the remaining data set, a factor-specific model fit at least as well as the best fitting common factor model. Three simulated data sets with known structure were then tested with a sequence of structural equation models. Common factor models could not always be falsified--even when they were false. In contrast, factor-specific models were more easily falsified when the true model included a unitary common factor. These results suggest that it is premature to conclude that all age-related cognitive declines are due to a single mechanism. Common factor models may be particularly difficult to falsify with current analytic procedures.