Endothelin-1 stimulates oral fibroblasts to promote oral cancer invasion

AbstractAimsThe aims of this study were to examine the role of endothelin-1 (ET-1), a pleiotropic peptide found at elevated levels in a number of malignancies and which has been shown to influence oral cancer cell behaviour via paracrine signalling pathways, on the phenotype of oral fibroblasts.Main methodsThe effect of ET-1 on proliferation and migration of human primary oral fibroblasts was assessed using MTS and scratch assays, respectively. The ability of ET-1 to affect fibroblast contractility was analysed using type-I collagen gels. Changes in gene expression in oral fibroblasts exposed to ET-1 were examined using quantitative PCR. The invasiveness of oral cancer cells in the presence of conditioned media collected from ET-1 treated fibroblasts was determined using 2D Matrigel assays.Key findingsHere we provide evidence that ET-1 increases the migration of oral fibroblasts and induces a more contractile phenotype which is not associated with changes in gene expression indicative of myofibroblast transdifferentiation. In addition we provide evidence that conditioned medium of ET-1-stimulated oral fibroblasts promotes invasion of OSCC cells in vitro.SignificanceIn oral squamous cell carcinoma, a frequently fatal and increasingly common epithelial malignancy of the oral cavity, ET-1 is known to contribute to pro-migratory paracrine signalling between stromal fibroblasts and cancer cells. The ability of ET-1 to modulate the phenotype of human oral stromal fibroblasts, however, has not previously been reported. The findings presented here suggest that targeting the stromal endothelin system may be a viable and novel therapeutic strategy for invasive oral cancer

Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies.

BACKGROUND: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. METHODS AND FINDINGS: We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels. CONCLUSIONS: Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa. Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions. In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required

Wildlife-friendly farming increases crop yield: evidence for ecological intensification

Ecological intensification has been promoted as a means to achieve environmentally sustainable increases in crop yields by enhancing ecosystem functions that regulate and support production. There is, however, little direct evidence of yield benefits from ecological intensification on commercial farms growing globally important foodstuffs (grains, oilseeds and pulses). We replicated two treatments removing 3 or 8% of land at the field edge from production to create wildlife habitat in 50–60 ha patches over a 900 ha commercial arable farm in central England, and compared these to a business as usual control (no land removed). In the control fields, crop yields were reduced by as much as 38% at the field edge. Habitat creation in these lower yielding areas led to increased yield in the cropped areas of the fields, and this positive effect became more pronounced over 6 years. As a consequence, yields at the field scale were maintained—and, indeed, enhanced for some crops—despite the loss of cropland for habitat creation. These results suggested that over a 5-year crop rotation, there would be no adverse impact on overall yield in terms of monetary value or nutritional energy. This study provides a clear demonstration that wildlife-friendly management which supports ecosystem services is compatible with, and can even increase, crop yields

Wildlife-friendly farming benefits rare birds, bees and plants

Agricultural intensification is a leading cause of global biodiversity loss, especially for threatened and near-threatened species. One widely implemented response is ‘wildlife-friendly farming’, involving the close integration of conservation and extensive farming practices within agricultural landscapes. However, the putative benefits from this controversial policy are currently either unknown or thought unlikely to extend to rare and declining species. Here, we show that new, evidence-based approaches to habitat creation on intensively managed farmland in England can achieve large increases in plant, bee and bird species. In particular, we found that habitat enhancement methods designed to provide the requirements of sensitive target biota consistently increased the richness and abundance of both rare and common species, with 10-fold to greater than 100-fold more rare species per sample area than generalized conventional conservation measures. Furthermore, targeting landscapes of high species richness amplified beneficial effects on the least mobile taxa: plants and bees. Our results provide the first unequivocal support for a national wildlife-friendly farming policy and suggest that this approach should be implemented much more extensively to address global biodiversity loss. However, to be effective, these conservation measures must be evidence-based, and developed using sound knowledge of the ecological requirements of key species

Capabilities of lidar- and satellite data in assessing the drivers of avian diversity in a fragmented landscape

In modern landscapes, small habitat patches such as woodlands isolated in an agricultural matrix, can be important refuges for wildlife. However, their value as habitat may be compromised by their size and thus knowledge of how habitat structure influences habitat quality is vital to maximize species diversity. This study examined the factors driving avian diversity in four small woods in an agricultural landscape, and how accurately remote sensing (RS) metrics were able to quantify this. Linear mixed-effect models were used to combine annual breeding bird census data with data of habitat structure from satellite images and airborne lidar. The aims were firstly to examine the drivers of bird diversity, and secondly to reveal the strengths and weaknesses of the compared RS datasets in quantifying them. The results showed that, at first, bird diversity increased significantly towards the edges, being driven in part by vegetation structure. The amount of understorey vegetation was the most significant driver of diversity, due to which lidar-based models outperformed satellite-based ones. In general, lidar metrics correlated strongly with bird diversity, but such relationships were not discovered with satellite image metrics. The results indicate that the drivers of diversity, especially in fragmented woodlands may be too fine-scaled to be studied without sufficient consideration of the structural component of vegetation, which was proven to be attainable from lidar data

Living on the edge: utilising lidar data to assess the importance of vegetation structure for avian diversity in fragmented woodlands and their edges

Context: In agricultural landscapes, small woodland patches can be important wildlife refuges. Their value in maintaining biodiversity may, however, be compromised by isolation, and so knowledge about the role of habitat structure is vital to understand the drivers of diversity. This study examined how avian diversity and abundance were related to habitat structure in four small woods in an agricultural landscape in eastern England. Objectives: The aims were to examine the edge effect on bird diversity and abundance, and the contributory role of vegetation structure. Specifically: what is the role of vegetation structure on edge effects, and which edge structures support the greatest bird diversity? Methods: Annual breeding bird census data for 28 species were combined with airborne lidar data in linear mixed models fitted separately at (i) the whole wood level, and (ii) for the woodland edges only. Results: Despite relatively small woodland areas (4.9–9.4 ha), bird diversity increased significantly towards the edges, being driven in part by vegetation structure. At the whole woods level, diversity was positively associated with increased vegetation above 0.5 m and especially with increasing vegetation density in the understorey layer, which was more abundant at the woodland edges. Diversity along the edges was largely driven by the density of vegetation below 4 m. Conclusions: The results demonstrate that bird diversity was maximised by a diverse vegetation structure across the wood and especially a dense understorey along the edge. These findings can assist bird conservation by guiding habitat management of remaining woodland patches

The MUK eight protocol: a randomised phase II trial of cyclophosphamide and dexamethasone in combination with ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor

Background Multiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD. Methods MUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This ‘switch’ phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment. Discussion Development of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safety and efficacy of ICD in patients with RRMM demonstrate a toxicity profile consistent with ixazomib in combination with lenalidomide and dexamethasone, whilst the combination showed possible activity in RRMM patients. Further investigation of the anti-tumour effect of this drug in RRMM patients is therefore warranted, especially since no trials comparing CD with ICD have been completed at present. Trial registration ISRCTN number: ISRCTN58227268. Registered on 26 August 2015

Adjuvant zoledronic acid reduces fractures in breast cancer patients; an AZURE (BIG 01/04) study

The fracture impact of adjuvant bisphosphonates in breast cancer is not defined with most trials reporting changes in bone mineral density as a surrogate. The AZURE trial (ISRCTN79831382) evaluated the impact of adjuvant zoledronic acid (ZOL) on fractures. The AZURE trial is an academic, multi-centre, randomised phase III study evaluating the addition of ZOL 4 mg to standard therapy (neo/adjuvant chemotherapy and/or endocrine therapy) for 5 years (administered by intravenous (iv) infusion every 3–4 weeks for 6 doses, then 3 monthly × 8 and 6 monthly × 5) in patients with stage II/III early breast cancer. Fracture data collected as part of skeletal-related adverse event reporting were analysed after a median of 84.2 months of follow-up and 966 disease-free survival (DFS) events. We assessed number of fractures, time- to-first fracture and the incidence of fractures before and after disease recurrence. Two hundred forty-four patients reported ≥1 fracture, 140 (8.3%) in the control arm (171 fractures) and 104 (6.2%) in the ZOL arm (120 fractures). Of the 291 fractures reported, 207 fractures occurred in the absence of recurrence (control 111, ZOL 96), 80 after recurrence (control 59, ZOL 21). The 5-year fracture rate was reduced from 5.9% (95%CI 4.8, 7.1%; control) to 3.8% (95%CI 2.9, 4.7%) with ZOL. ZOL significantly increased time-to-first fracture (HR 0.69, 95%CI 0.53–0.90; P = 0.0053) but the majority of fracture prevention benefit occurred after a DFS event (HR 0.3; 95%CI 0.17, 0.53; P < 0.001). Fracture benefits from ZOL were similar across menopausal sub-groups. In conclusion, adjuvant ZOL reduced the risk of clinical fractures, the majority of this protection occurred after disease recurrence

Morphology, geographical variation and the subspecies of marsh tit Poecile palustris in Britain and central Europe

Capsule: All British Marsh Tits belong to subspecies Poecile palustris dresseri, being smaller than nominate P. p. palustris of central Europe. Aims: Determining the subspecies of Marsh Tit in Britain to test whether ssp. P. p. palustris occurs in northern England and Scotland, by assessing regional variation in size compared with central European birds. Methods: 1147 wing length and 250 tail length measurements from 953 Marsh Tits were compared between eight British locations to test for regional variation. Biometrics were compared between birds from Britain and six locations within the continental European range of ssp. palustris. Results: There was no regional variation in wing or tail lengths among British Marsh Tits, indicating that all resident birds belong to ssp. dresseri. There was no evidence supporting the existence of ssp. palustris in northern England. British birds were significantly smaller than those from continental Europe, with proportionately shorter tails, consistent across all age and sex classes. Conclusion: All British Marsh Tits should be considered as ssp. dresseri, with ssp. palustris being limited to continental Europe. With no evidence of regional variation in size within Britain, reliable sexing methods based on biometrics could be applied in demographic studies throughout the country

Report 8: Symptom progression of COVID-19

The COVID-19 epidemic was declared a Public Health Emergency of International Concern (PHEIC) by WHO on 30th January 2020 [1]. As of 8 March 2020, over 107,000 cases had been reported. Here, we use published and preprint studies of clinical characteristics of cases in mainland China as well as case studies of individuals from Hong Kong, Japan, Singapore and South Korea to examine the proportional occurrence of symptoms and the progression of symptoms through time. We find that in mainland China, where specific symptoms or disease presentation are reported, pneumonia is the most frequently mentioned, see figure 1. We found a more varied spectrum of severity in cases outside mainland China. In Hong Kong, Japan, Singapore and South Korea, fever was the most frequently reported symptom. In this latter group, presentation with pneumonia is not reported as frequently although it is more common in individuals over 60 years old. The average time from reported onset of first symptoms to the occurrence of specific symptoms or disease presentation, such as pneumonia or the use of mechanical ventilation, varied substantially. The average time to presentation with pneumonia is 5.88 days, and may be linked to testing at hospitalisation; fever is often reported at onset (where the mean time to develop fever is 0.77 days)