Permanent grasslands in Europe : Land use change and intensification decrease their multifunctionality

Acknowledgments We acknowledge the financial support of this work by European Union Horizon 2020 research and innovation programme, under grant agreement 774124, project SUPER-G (Developing Sustainable Permanent Grassland Systems and Policies).Peer reviewedPublisher PD

A G316A polymorphism in the ornithine decarboxylase gene promoter modulates MYCN-driven childhood neuroblastoma

Simple Summary Neuroblastoma is a devasting childhood cancer in which multiple copies (amplification) of the cancer-causing gene MYCN strongly predict poor outcome. Neuroblastomas are reliant on high levels of cellular components called polyamines for their growth and malignant behavior, and the gene regulating polyamine synthesis is called ODC1. ODC1 is often coamplified with MYCN, and in fact is regulated by MYCN, and like MYCN is prognostic of poor outcome. Here we studied a naturally occurring genetic variant or polymorphism that occurs in the ODC1 gene, and used gene editing to demonstrate the functional importance of this variant in terms of ODC1 levels and growth of neuroblastoma cells. We showed that this variant impacts the ability of MYCN to regulate ODC1, and that it also influences outcome in neuroblastoma, with the rarer variant associated with a better survival. This study addresses the important topic of genetic polymorphisms in cancer. Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of ODC1, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype MYCN-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased ODC1 expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the ODC1 promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in MYCN-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the ODC1 G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein

A scoping review of research on complementary and alternative medicine (CAM) and the mass media: Looking back, moving forward

<p>Abstract</p> <p>Background</p> <p>The use of complementary and alternative medicine (CAM) has become more common in Western developed countries in recent years, as has media reporting on CAM and related issues. Correspondingly, media reports are a primary information source regarding decisions to use CAM. Research on CAM related media reports is becoming increasingly relevant and important; however, identifying key concepts to guide future research is problematic due to the dispersed nature of completed research in this field. A scoping review was conducted to: 1) determine the amount, focus and nature of research on CAM and the mass media; and 2) summarize and disseminate related research results.</p> <p>Methods</p> <p>The main phases were: 1) searching for relevant studies; 2) selecting studies based on pre-defined inclusion criteria; 3) extracting data; and 4) collating, summarizing and reporting the results.</p> <p>Results</p> <p>Of 4,454 studies identified through various search strategies, 16 were relevant to our objectives and included in a final sample. CAM and media research has focused primarily on print media coverage of a range of CAM therapies, although only a few studies articulated differences within the range of therapies surveyed. Research has been developed through a variety of disciplinary perspectives, with a focus on representation research. The research reviewed suggests that journalists draw on a range of sources to prepare media reports, although most commonly they cite conventional (versus CAM) sources and personal anecdotes. The tone of media reports appears generally positive, which may be related to a lack of reporting on issues related to risk and safety. Finally, a variety of discourses within media representations of CAM are apparent that each appeal to a specific audience through resonance with their specific concerns.</p> <p>Conclusion</p> <p>Research on CAM and the mass media spans multiple disciplines and strategies of inquiry; however, despite the diversity in approach, it is clear that issues related to production and reception of media content are in need of research attention. To address the varied issues in a comprehensive manner, future research needs to be collaborative, involving researchers across disciplines, journalists and CAM users.</p

MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4

Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4) has been reported to be a direct transcriptional target of MYC. We show for the first time that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome. siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells led to inhibition of cell proliferation and migration. Chromatin immunoprecipitation assay demonstrated that TFAP4 expression is positively regulated by MYCN. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study suggests a regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying potential therapeutic targets for aggressive forms of this disease

Altered Expression of Insulin Receptor Isoforms in Breast Cancer

PURPOSE: Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies. EXPERIMENTAL DESIGN: mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized. RESULTS: The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes. CONCLUSIONS: The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic

Within-Host Dynamics of the Hepatitis C Virus Quasispecies Population in HIV-1/HCV Coinfected Patients

HIV/HCV coinfected individuals under highly active antiretroviral therapy (HAART) represent an interesting model for the investigation of the role played by the immune system in driving the evolution of the HCV quasispecies. We prospectively studied the intra-host evolution of the HCV heterogeneity in 8 coinfected subjects, selected from a cohort of 32 patients initiating HAART: 5 immunological responders (group A) and 3 immunological non-responders (group B), and in two HCV singly infected controls not assuming drugs (group C). For all these subjects at least two serial samples obtained at the first observation (before HAART) and more than 1 year later, underwent clonal sequence analysis of partial E1/E2 sequences, encompassing the whole HVR1. Evolutionary rates, dated phylogenies and population dynamics were co-estimated by using a Bayesian Markov Chain Monte Carlo approach, and site specific selection pressures were estimated by maximum likelihood-based methods. The intra-host evolutionary rates of HCV quasispecies was 10 times higher in subjects treated with HAART than in controls without immunodeficiency (1.9 and 2.3×10−3 sub/site/month in group A and B and 0.29×10−3 sub/site/month in group C individuals). The within-host Bayesian Skyline plot analysis showed an exponential growth of the quasispecies populations in immunological responders, coinciding with a peak in CD4 cell counts. On the contrary, quasispecies population remained constant in group B and in group C controls. A significant positive selection pressure was detected in a half of the patients under HAART and in none of the group C controls. Several sites under significant positive selection were described, mainly included in the HVR1. Our data indicate that different forces, in addition to the selection pressure, drive an exceptionally fast evolution of HCV during HAART immune restoration. We hypothesize that an important role is played by the enlargement of the viral replicative space

Permanent grasslands in Europe: Land use change and intensification decrease their multifunctionality

Permanent grasslands cover 34% of the European Union's agricultural area and are vital for a wide variety of ecosystem services essential for our society. Over recent decades, the permanent grassland area has declined and land use change continues to threaten its extent. Simultaneously, the management intensity of permanent grasslands increased. We performed a systematic literature review on the multifunctionality of permanent grasslands in Europe, examining the effects of land use and management on 19 grassland ecosystem service indicators. Based on the evidence in 696 out of 70,456 screened papers, published since 1980, we found that both land use change and intensification of management decreased multifunctionality. In particular, preventing conversion of permanent grasslands to croplands secured the delivery of multiple ecosystem services. A lower management intensity was associated with benefits for biodiversity, climate regulation and water purification, but impacted the provision of high-quality animal feed. Increasing the number of species in the sward enhanced multifunctionality of permanent grassland without significant trade-offs such as losses in production. Our review covered many aspects of land use, management and ecosystem services, but we also identified areas with no or only few studies. The most prominent gaps were related to comparisons between permanent and temporary grasslands, and effects of management practices on the provision of cultural values, and on erosion and flood control. We suggest that, despite apparent changes in human dietary preferences, the protection of permanent grasslands in Europe must be prioritised. At the same time, considering the need to reduce ruminant livestock's contribution to climate change, the time seems ripe to increase support for low-intensity grassland management to optimise the provision of essential ecosystem services from Europe's permanent grasslands

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in&nbsp;vitro, as well as more metastatic in&nbsp;vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis