Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis

The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p < 0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71-5.25) and early recurrence (HR = 2.89, 95% CI 1.67-4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57). These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study

Variation in a Darwin Wasp (Hymenoptera: Ichneumonidae) Community along an Elevation Gradient in a Tropical Biodiversity Hotspot: Implications for Ecology and Conservation

Understanding how biodiversity varies from place to place is a fundamental goal of ecology and an important tool for halting biodiversity loss. Parasitic wasps (Hymenoptera) are a diverse and functionally important animal group, but spatial variation in their diversity is poorly understood. We survey a community of parasitic wasps (Ichneumonidae: Pimplinae) using Malaise traps up a mountain in the Brazilian Atlantic Rainforest, and relate the catch to biotic and abiotic habitat characteristics. We find high species richness compared with previous similar studies, with abundance, richness, and diversity peaking at low to intermediate elevation. There is a marked change in community composition with elevation. Habitat factors strongly correlated with elevation also strongly predict changes in the pimpline community, including temperature as well as the density of bamboo, lianas, epiphytes, small trees, and herbs. These results identify several possible surrogates of pimpline communities in tropical forests, which could be used as a tool in conservation. They also contribute to the growing evidence for a typical latitudinal gradient in ichneumonid species richness, and suggest that low to medium elevations in tropical regions will sometimes conserve the greatest number of species locally, but to conserve maximal biodiversity, a wider range of elevations should also be targeted

Behaviour change interventions to reduce second-hand smoke (SHS) exposure at home in pregnant women - A systematic review and intervention appraisal

Abstract Background Second-hand smoke (SHS) exposure during pregnancy is associated with poor pregnancy and foetal outcomes. Theory-based behaviour change interventions (BCI) have been used successfully to change smoking related behaviours and offer the potential to reduce exposure of SHS in pregnant women. Systematic reviews conducted so far do not evaluate the generalisability and scalability of interventions. The objectives of this review were to (1) report the BCIs for reduction in home exposure to SHS for pregnant women; and (2) critically appraise intervention-reporting, generalisability, feasibility and scalability of the BCIs employed. Methods Standard methods following PRISMA guidelines were employed. Eight databases were searched from 2000 to 2015 in English. The studies included used BCIs on pregnant women to reduce their home SHS exposure by targeting husbands/partners. The Workgroup for Intervention Development and Evaluation Research (WIDER) guidelines were used to assess intervention reporting. Generalisability, feasibility and scalability were assessed against criteria described by Bonell and Milat. Results Of 3479 papers identified, six studies met the inclusion criteria. These studies found that BCIs led to increased knowledge about SHS harms, reduction or husbands quitting smoking, and increased susceptibility and change in level of actions to reduce SHS at home. Two studies reported objective exposure measures, and one reported objective health outcomes. The studies partially followed WIDER guidelines for reporting, and none met all generalisability, feasibility and scalability criteria. Conclusions There is a dearth of literature in this area and the quality of studies reviewed was moderate to low. The BCIs appear effective in reducing SHS, however, weak study methodology (self-reported exposure, lack of objective outcome assessment, short follow-up, absence of control group) preclude firm conclusion. Some components of the WIDER checklist were followed for BCI reporting, scalability and feasibility of the studies were not described. More rigorous studies using biochemical and clinical measures for exposures and health outcomes in varied study settings are required. Studies should report interventions in detail using WIDER checklist and assess them for generalisability, feasibility and scalability. Trial registration CRD40125026666

Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial.

AIMS: Long-standing persistent atrial fibrillation (LSPAF) is challenging to treat with suboptimal catheter ablation (CA) outcomes. Thoracoscopic surgical ablation (SA) has shown promising efficacy in atrial fibrillation (AF). This multicentre randomized controlled trial tested whether SA was superior to CA as the first interventional strategy in de novo LSPAF. METHODS AND RESULTS: We randomized 120 LSPAF patients to SA or CA. All patients underwent predetermined lesion sets and implantable loop recorder insertion. Primary outcome was single procedure freedom from AF/atrial tachycardia (AT) ≥30 s without anti-arrhythmic drugs at 12 months. Secondary outcomes included clinical success (≥75% reduction in AF/AT burden); procedure-related serious adverse events; changes in patients' symptoms and quality-of-life scores; and cost-effectiveness. At 12 months, freedom from AF/AT was recorded in 26% (14/54) of patients in SA vs. 28% (17/60) in the CA group [OR 1.128, 95% CI (0.46-2.83), P = 0.83]. Reduction in AF/AT burden ≥75% was recorded in 67% (36/54) vs. 77% (46/60) [OR 1.13, 95% CI (0.67-4.08), P = 0.3] in SA and CA groups, respectively. Procedure-related serious adverse events within 30 days of intervention were reported in 15% (8/55) of patients in SA vs. 10% (6/60) in CA, P = 0.46. One death was reported after SA. Improvements in AF symptoms were greater following CA. Over 12 months, SA was more expensive and provided fewer quality-adjusted life-years (QALYs) compared with CA (0.78 vs. 0.85, P = 0.02). CONCLUSION: Single procedure thoracoscopic SA is not superior to CA in treating LSPAF. Catheter ablation provided greater improvements in symptoms and accrued significantly more QALYs during follow-up than SA. CLINICAL TRIAL REGISTRATION: ISRCTN18250790 and ClinicalTrials.gov: NCT02755688

Physical activity, sedentary time and physical capability in early old age: British birth cohort study.

PURPOSE: To investigate the associations of time spent sedentary, in moderate-to-vigorous-intensity physical activity (MVPA) and physical activity energy expenditure (PAEE) with physical capability measures at age 60-64 years. METHODS: Time spent sedentary and in MVPA and, PAEE were assessed using individually calibrated combined heart rate and movement sensing among 1727 participants from the MRC National Survey of Health and Development in England, Scotland and Wales as part of a detailed clinical assessment undertaken in 2006-2010. Multivariable linear regression models were used to examine the cross-sectional associations between standardised measures of each of these behavioural variables with grip strength, chair rise and timed up-&-go (TUG) speed and standing balance time. RESULTS: Greater time spent in MVPA was associated with higher levels of physical capability; adjusted mean differences in each capability measure per 1 standard deviation increase in MVPA time were: grip strength (0.477 kg, 95% confidence interval (CI): 0.015 to 0.939), chair rise speed (0.429 stands/min, 95% CI: 0.093 to 0.764), standing balance time (0.028 s, 95% CI: 0.003 to 0.053) and TUG speed (0.019 m/s, 95% CI: 0.011 to 0.026). In contrast, time spent sedentary was associated with lower grip strength (-0.540 kg, 95% CI: -1.013 to -0.066) and TUG speed (-0.011 m/s, 95% CI: -0.019 to -0.004). Associations for PAEE were similar to those for MVPA. CONCLUSION: Higher levels of MVPA and overall physical activity (PAEE) are associated with greater levels of physical capability whereas time spent sedentary is associated with lower levels of capability. Future intervention studies in older adults should focus on both the promotion of physical activity and reduction in time spent sedentary.This work was supported by the UK Medical Research Council (U120063239, U123092720, MC_UU_12019/1, MC_UU_12019/4, MC_UU_12015/3, and MC_UU_12015/4).This is the final published version. It first appeared at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126465

Experimental Infection of Mice with Avian Paramyxovirus Serotypes 1 to 9

The nine serotypes of avian paramyxoviruses (APMVs) are frequently isolated from domestic and wild birds worldwide. APMV-1, also called Newcastle disease virus, was shown to be attenuated in non-avian species and is being developed as a potential vector for human vaccines. In the present study, we extended this evaluation to the other eight serotypes by evaluating infection in BALB/c mice. Mice were inoculated intranasally with a prototype strain of each of the nine serotypes and monitored for clinical disease, gross pathology, histopathology, virus replication and viral antigen distribution, and seroconversion. On the basis of multiple criteria, each of the APMV serotypes except serotype 5 was found to replicate in mice. Five of the serotypes produced clinical disease and significant weight loss in the following order of severity: 1, 2>6, 9>7. However, disease was short-lived. The other serotypes produced no evident clinical disease. Replication of all of the APMVs except APMV-5 in the nasal turbinates and lungs was confirmed by the recovery of infectious virus and by substantial expression of viral antigen in the epithelial lining detected by immunohistochemistry. Trace levels of infectious APMV-4 and -9 were detected in the brain of some animals; otherwise, no virus was detected in the brain, small intestine, kidney, or spleen. Histologically, infection with the APMVs resulted in lung lesions consistent with broncho-interstitial pneumonia of varying severity that were completely resolved at 14 days post infection. All of the mice infected with the APMVs except APMV-5 produced serotype-specific HI serum antibodies, confirming a lack of replication of APMV-5. Taken together, these results demonstrate that all APMV serotypes except APMV-5 are capable of replicating in mice with minimal disease and pathology

PKCη promotes a proliferation to differentiation switch in keratinocytes via upregulation of p27Kip1 mRNA through suppression of JNK/c-Jun signaling under stress conditions

To maintain epidermal homeostasis, the balance between keratinocyte proliferation and differentiation is tightly controlled. However, the molecular mechanisms underlying this balance remain unclear. In 3D organotypic coculture with mouse keratinocytes and fibroblasts, the thickness of stratified cell layers was prolonged, and growth arrest and terminal differentiation were delayed when PKCη-null keratinocytes were used. Re-expression of PKCη in PKCη-null keratinocytes restored stratified cell layer thickness, growth arrest and terminal differentiation. We show that in 3D cocultured PKCη-null keratinocytes, p27Kip1 mRNA was downregulated, whereas JNK/c-Jun signaling was enhanced. Furthermore, inhibition of JNK/c-Jun signaling in PKCη-null keratinocytes led to upregulation of p27Kip1 mRNA, and to thinner stratified cell layers. Collectively, our findings indicate that PKCη upregulates p27Kip1 mRNA through suppression of JNK/c-Jun signaling. This results in promoting a proliferation to differentiation switch in keratinocytes

SRA-Domain Proteins Required for DRM2-Mediated De Novo DNA Methylation

De novo DNA methylation and the maintenance of DNA methylation in asymmetrical sequence contexts is catalyzed by homologous proteins in plants (DRM2) and animals (DNMT3a/b). In plants, targeting of DRM2 depends on small interfering RNAs (siRNAs), although the molecular details are still unclear. Here, we show that two SRA-domain proteins (SUVH9 and SUVH2) are also essential for DRM2-mediated de novo and maintenance DNA methylation in Arabidopsis thaliana. At some loci, SUVH9 and SUVH2 act redundantly, while at other loci only SUVH2 is required, and this locus specificity correlates with the differing DNA-binding affinity of the SRA domains within SUVH9 and SUVH2. Specifically, SUVH9 preferentially binds methylated asymmetric sites, while SUVH2 preferentially binds methylated CG sites. The suvh9 and suvh2 mutations do not eliminate siRNAs, suggesting a role for SUVH9 and SUVH2 late in the RNA-directed DNA methylation pathway. With these new results, it is clear that SRA-domain proteins are involved in each of the three pathways leading to DNA methylation in Arabidopsis

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.Peer reviewe