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The effects of tree shelters on the survival, height and diameter growth of three coniferous tree species – Scots pine (Pinus sylvestris L.), Norway spruce (Picea abies (L.) H. Karst.) and Silver fir (Abies alba Mill.) were observed. The study was conducted in two experimental plantations, established in the spring of 2016 in the Training and Experimental Forest Range Jundola (Central South Bulgaria). Three experimental variants with tree shelters – Tubex Ventex Classic, Layflat Shelterguard, Layflat Treeguard and a control one (without tree shelters) were used. Twenty to twenty-five seedlings in three replications of each variant and tree species were planted. The experimental plantation 1 included Scots pine and Norway spruce and was established on a south east-facing terrain at an altitude of 1400 m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist. The experimental plantation 2 is of Silver fir and was located on an east-facing terrain at an altitude of 1400 m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist to moist. In the autumn of the fifth year after the establishment, inventories and measurements of heights, height increment and groundline diameter of the seedlings were made. The survival in both experimental plantations was higher in the variants with tree shelter. The height growth of all tree species was better in tree shelter variants, with the highest average height in the variant with Tubex Ventex Classic. The biggest height increment was established in the variant with Layflat Shelterguard for Norway spruce and Silver fir and in variant without tree shelters for Scots pine. The ground line diameter was highest in control variant for Scots pine and Norway spruce and in the variant with Layflat Treegard for the Silver fir.

The effects of tree shelters on the survival, height, and diameter growth of three deciduous tree species – common beech (Fagus sylvatica L.), sycamore (Acer pseudoplatanus L.) and sessile oak (Quercus petraea Matt. (Liebl.) were studied. The study was conducted in two experimental plantations, established in the spring of 2018 in the Training and Experimental Forest Range Petrohan (North-Western Bulgaria). Four experimental variants with tree shelters – Tubex Ventex Classic, Tubex Ventex Clear, Layflat Shelterguard, Layflat Treeguard and a control one (without tree shelters) were used. Twenty to twenty-seven seedlings in three replications of each variant and tree species were planted. The experimental plantation-1 was established on an east-facing flat terrain at an altitude of 600 m. The soil is Grey Luvisol mixture of sandy and clay, slightly stony, and very deep. The site class is medium rich to rich. The experimental plantation-2 is located in a high-density game area. The area is a meadow, aspect north, slope with gradient 8o and an altitude of 850 m. The soil is Dystric-Eutric Cambisol, mixture of sandy and clay, slightly stony and deep. The site class is medium rich to rich. In the autumn of the second and third year after the planting height, height increment and root collar diameter were measured. The survival in both experimental plantations was high but without any statistical significance of the tree shelter. The height growth of all tree species was better in tree shelter variants, with the highest average in that with Tubex Ventex Clear. The root collar diameter growth was not yet significantly affected by the use of tree shelters. As a result of research, ventilated tree shelters (Tubex Ventex Classic and Tubex Ventex Clear) may be recommended as suitable.

Characteristics of the eight case vignettes used in this survey. (DOCX 18 kb)

Showing MCL-1 mRNA levels do not change in Her2-positive BC cells under hypoxic conditions. Figure S2 showing a Bcl-2 is expressed in both Mcl-1wt/wt and Mcl-1Î /null MEFs. Whole-cell extracts were analyzed by immunoblotting with indicated antibodies. Immunoblotting for Erk2 confirmed equal protein loading. b EU-5346 does not change Mcl-1 mRNA expression in Her2-positive BC cells under hypoxic conditions. Figure S3 showing Mcl-1 is a potential therapeutic target not only in Her2-positive, but also in Luminal A-like and TNBC cells under hypoxic conditions. (PDF 1580 kb)

MEK/ERK and NF-kB signaling pathways have been reported to play a key role in multiple myeloma (MM) survival, proliferation and drug resistance. These pathways regulate the activity of numerous transcription factors. For example, the activator protein-1 (AP-1) transcription factor has been implicated in a multitude of physiologic processes, but also tumorigenesis. However, the function of AP-1 in MM is largely unknown. Our data show a vast variety of AP-1 (c-Jun, JunB, JunD, c-Maf and c-Fos) expression levels in MM cells. Importantly, co-culture of MM cells with bone marrow stromal cells (BMSCs), i.e. isotypic primary BMSCs as well as BMSC lines KM-105 and HS-27A, rapidly and strongly induces expression of JunB, but not other AP-1 members. Previous studies have shown that JunB exerts opposite functions depending on the cellular origin and the physiopathological context. For example, it serves as a gatekeeper in acute and chronic myeloid leukemia, but as a positive regulator in Hodgkin's lymphomas and anaplastic large cell lymphomas. The relevance of JunB activity in MM growth, survival and drug resistance is elusive. First, our data demonstrate that induction of JunB is predominantly mediated by soluble factors secreted by BMSCs rather than direct MM-BMSC contact. Indeed, using cytokine arrays, we identified IL-6 among the most potent factors that trigger JunB expression. Mechanistically, JunB upregulation occurs at both transcriptional as well as translational level. Pharmacologic inhibition was used next in order to identify upstream signaling pathways, which mediate BMSC- induced JunB upregulation in MM cells. Our data show that activation of MEK/ERK or NF-kB is required for induction of JunB expression and AP-1 transcriptional activity. To delineate the specific functional role of JunB in MM pathogenesis, we transduced MM cells with pLKO.1-JunB shRNA or pLKO.1-scrambled shRNA (SCR). After puromycin- selection, effects of JunB knockdown on MM proliferation, survival and drug resistance were analyzed by 3H-thymidine incorporation, flow cytometry and western blot. Indeed, we observed significant inhibition of proliferation in MM/ JunB shRNA (decreased to ~ 25 – 40 %, p < 0.01) compared with MM/ SCR control cells, when co-cultured with BMSCs in particular. Moreover, our preliminary data show that knockdown of JunB overcomes resistance of MM cells against doxorubicin as well as melphalan. Furthermore, 4-hydroxytamoxifen (4-OHT) treatment of MM cell lines stably transduced with pMSCV-JunB-ER-IRES-GFP but not pMSCV-IRES-GFP induced significant AP-1 luciferase activity (~ 3.3 fold, p < 0.01) as well as MM cell proliferation. In ongoing experiments, the in vivo relevance of our in vitro data is evaluated in a xenograft mouse model inoculated with MM /JunB-ER-IRES-GFP and MM/ IRES-GFP cells. Finally, gene expression profiles on > 1000 MM patient samples of different prognostic groups were compared to samples from healthy donors using the gene set enrichment analysis (GSEA). Our results further support a key role for JunB in MM pathogenesis. In summary, our data demonstrate for the first time an important role of JunB/AP-1 in MM tumorigenesis and strongly propose it as a novel therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.

Participating countries: number of invited GPs and response rates per country. (DOCX 21 kb)

BACKGROUND General practitioners (GPs) should regularly review patients' medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients' health. However, deprescribing can be challenging for physicians. This study investigates GPs' deprescribing decisions in 31 countries. METHODS In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs' deprescribing decisions. RESULTS Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). INTERPRETATION The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.

Survey. (DOCX 49 kb)

Additional file 1. Appendix 1-3.

Participating countries: number of invited GPs and response rates per country. (DOCX 21 kb)

Survey. (DOCX 49 kb)