A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma

SIMPLE SUMMARY: Malignant pleural mesothelioma (MPM) is a disease of the pleura related to asbestos exposure. Despite the advancements in new therapeutic frontiers, it has a dismal prognosis and very limited treatment options. To find novel weapons in the care of MPM, we undertook a drug-repurposing approach that consists of evaluating existing drugs already approved for other human diseases. We screened 1170 drugs, and we observed that cephalomannine, a taxane; ouabain, a cardiac glycoside; thonzonium bromide, an antifungal surfactant; and emetine, an emetic alkaloid, had marked activity against immortalized and patient-derived primary MPM cell lines. These compounds were shown to be promising, and they will be evaluated in further studies, both in vitro and in vivo. We believe that drug repurposing is a valuable strategy to facilitate and accelerate the definition of novel treatment options for the management of MPM. ABSTRACT: The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines. Biological assays were carried out for 41 drugs, showing the highest cytotoxicity and for whom there were a complete lack of published literature in MPM. Cytotoxicity and caspase activation were evaluated with commercially available kits and cell proliferation was assayed using MTT assay and by clonogenic activity with standard protocols. Moreover, the five most effective drugs were further evaluated on patient-derived primary MPM cell lines. The most active molecules were cephalomannine, ouabain, alexidine, thonzonium bromide, and emetine. Except for alexidine, these drugs inhibited the clonogenic ability and caspase activation in all cancer lines tested. The proliferation was inhibited also on an extended panel of cell lines, including primary MPM cells. Thus, we suggest that cephalomannine, ouabain, thonzonium bromide, and emetine could represent novel candidates to be repurposed for improving the arsenal of therapeutic weapons in the fight against MPM

A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma

Simple Summary Malignant pleural mesothelioma (MPM) is a disease of the pleura related to asbestos exposure. Despite the advancements in new therapeutic frontiers, it has a dismal prognosis and very limited treatment options. To find novel weapons in the care of MPM, we undertook a drug-repurposing approach that consists of evaluating existing drugs already approved for other human diseases. We screened 1170 drugs, and we observed that cephalomannine, a taxane; ouabain, a cardiac glycoside; thonzonium bromide, an antifungal surfactant; and emetine, an emetic alkaloid, had marked activity against immortalized and patient-derived primary MPM cell lines. These compounds were shown to be promising, and they will be evaluated in further studies, both in vitro and in vivo. We believe that drug repurposing is a valuable strategy to facilitate and accelerate the definition of novel treatment options for the management of MPM. The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines. Biological assays were carried out for 41 drugs, showing the highest cytotoxicity and for whom there were a complete lack of published literature in MPM. Cytotoxicity and caspase activation were evaluated with commercially available kits and cell proliferation was assayed using MTT assay and by clonogenic activity with standard protocols. Moreover, the five most effective drugs were further evaluated on patient-derived primary MPM cell lines. The most active molecules were cephalomannine, ouabain, alexidine, thonzonium bromide, and emetine. Except for alexidine, these drugs inhibited the clonogenic ability and caspase activation in all cancer lines tested. The proliferation was inhibited also on an extended panel of cell lines, including primary MPM cells. Thus, we suggest that cephalomannine, ouabain, thonzonium bromide, and emetine could represent novel candidates to be repurposed for improving the arsenal of therapeutic weapons in the fight against MPM

Obesity and the Risk of Papillary Thyroid Cancer: A Pooled Analysis of Three Case-Control Studies.

Background: There is a correlation between temporal trends of obesity prevalence and papillary thyroid cancer (PTC) incidence in the United States. Obesity is a well-recognized risk factor for many cancers, but there are few studies on the association between obesity and PTC risk. We investigated the association between anthropometric measurements and PTC risk using pooled individual data from three case–control populations. Methods: Height and weight information were obtained from three independent case–control studies, including 1917 patients with PTC (1360 women and 557 men) and 2127 cancer-free controls from the United States, Italy, and Germany. Body mass index (BMI), body fat percentage, and body surface area (BSA) were calculated. An unconditional logistic regression model was used to calculate odds ratios (ORs) and confidence intervals (CIs) with respect to risk of PTC, adjusted by age, sex, race/ethnicity, and study site. Results: In the pooled population, for both men and women, an increased risk of PTC was found to be associated with greater weight, BMI, body fat percentage, and BSA, whereas a reduced risk of PTC was associated with greater height, in the pooled population for both men and women. Compared with normal-weight subjects (BMI 18.5–24.9 kg/m2), the ORs for overweight (BMI 25–29.9 kg/m2) and obese (BMI ‡ 30 kg/m2) subjects were 1.72 [CI 1.48–2.00] and 4.17 [CI 3.41–5.10] respectively. Compared with the lowest quartile of body fat percentage, the ORs for the highest quartile were 3.83 [CI 2.85–5.15] in women and 4.05 [CI 2.67– 6.15] in men. Conclusion: Anthropometric factors, especially BMI and body fat percentage, were significantly associated with increased risk of PTC. Future studies of anthropometric factors and PTC that incorporate intermediate factors, including adiposity and hormone biomarkers, are essential to help clarify potential mechanisms of the relationship

An Improved and Homogeneous Altimeter Sea Level Record from the ESA Climate Change Initiative

Sea Level is a very sensitive index of climate change since it integrates the impacts of ocean warming and ice mass loss from glaciers and the ice sheets. Sea Level has been listed as an Essential Climate Variable (ECV) by the Global Climate Observing System (GCOS). During the past 25 years, the sea level ECV has been measured from space by different altimetry missions that have provided global and regional observations of sea level variations. As part of the Climate Change Initiative (CCI) program of the European Space Agency (ESA) (established in 2010), the Sea Level project (SL_cci) aimed at providing an accurate and homogeneous long-term satellite-based sea level record. At the end of the first phase of the project (2010-2013), an initial version (v1.1) of the sea level ECV has been made available to users (Ablain et al., 2015). During the second phase (2014-2017), improved altimeter standards have been selected to produce new sea level products (called SL_cci v2.0) based on 9 altimeter missions for the period 1993-2015 (https://doi.org/10.5270/esa-sea_level_cci-1993_2015-v_2.0-201612). Corresponding orbit solutions, geophysical corrections and altimeter standards used in this v2.0 dataset are described in details in Quartly et al. (2017). The present paper focuses on the description of the SL_cci v2.0 ECV and associated uncertainty and discusses how it has been validated. Various approaches have been used for the quality assessment such as internal validation, comparisons with sea level records from other groups and with in-situ measurements, sea level budget closure analyses and comparisons with model outputs. Compared to the previous version of the sea level ECV, we show that use of improved geophysical corrections, careful bias reduction between missions and inclusion of new altimeter missions lead to improved sea level products with reduced uncertainties at different spatial and temporal scales. However, there is still room for improvement since the uncertainties remain larger than the GCOS requirements. Perspectives for subsequent evolutions are also discussed

A new phase in the production of quality-controlled sea level data

Sea level is an essential climate variable (ECV) that has a direct effect on many people through inundations of coastal areas, and it is also a clear indicator of climate changes due to external forcing factors and internal climate variability. Regional patterns of sea level change inform us on ocean circulation variations in response to natural climate modes such as El Niño and the Pacific Decadal Oscillation, and anthropogenic forcing. Comparing numerical climate models to a consistent set of observations enables us to assess the performance of these models and help us to understand and predict these phenomena, and thereby alleviate some of the environmental conditions associated with them. All such studies rely on the existence of long-term consistent high-accuracy datasets of sea level. The Climate Change Initiative (CCI) of the European Space Agency was established in 2010 to provide improved time series of some ECVs, including sea level, with the purpose of providing such data openly to all to enable the widest possible utilisation of such data. Now in its second phase, the Sea Level CCI project (SL_cci) merges data from nine different altimeter missions in a clear, consistent and well-documented manner, selecting the most appropriate satellite orbits and geophysical corrections in order to further reduce the error budget. This paper summarises the corrections required, the provenance of corrections and the evaluation of options that have been adopted for the recently released v2.0 dataset (https://doi.org/10.5270/esa-sea_level_cci-1993_2015-v_2.0-201612). This information enables scientists and other users to clearly understand which corrections have been applied and their effects on the sea level dataset. The overall result of these changes is that the rate of rise of global mean sea level (GMSL) still equates to ∼ 3.2 mm yr−1 during 1992–2015, but there is now greater confidence in this result as the errors associated with several of the corrections have been reduced. Compared with v1.1 of the SL_cci dataset, the new rate of change is 0.2 mm yr−1 less during 1993 to 2001 and 0.2 mm yr−1 higher during 2002 to 2014. Application of new correction models brought a reduction of altimeter crossover variances for most corrections

Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines

Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity resistant to chemotherapy. The identification of novel therapeutic targets is needed to improve its poor prognosis. Following a review of literature and a screening of specimens we found that platelet-derived growth factor receptor beta (PDGFRB) is over-expressed, but not somatically mutated, in MPM tissues. We aimed to ascertain whether PDGFRB is a MPM-cancer driver gene. The approaches employed included the use of gene silencing and the administration of small molecules, such as crenolanib and imatinib (PDGFR inhibitors) on MPM cell lines (IstMes2, Mero-14, Mero-25). Met5A cells were used as non-malignant mesothelial cell line. PDGFRB-silencing caused a decrease in the proliferation rate, and a reduced colony formation capacity, as well as an increase of the share of cells in sub-G1 and in G2 phase, and increased apoptotic rate of MPM cell lines. Loss of migration ability was also observed. Similar, or even further enhanced, results were obtained with crenolanib. Imatinib showed the least effective activity on the phenotype. In conclusion, our study highlights PDGFRB as target with a clear role in MPM tumorigenesis and provided a rationale to explore further the efficacy of crenolanib in MPM patients, with promising results

Jasmonic Acid-Induced Changes in Brassica oleracea Affect Oviposition Preference of Two Specialist Herbivores

Jasmonic acid (JA) is a key hormone involved in plant defense responses. The effect of JA treatment of cabbage plants on their acceptability for oviposition by two species of cabbage white butterflies, Pieris rapae and P. brassicae, was investigated. Both butterfly species laid fewer eggs on leaves of JA-treated plants compared to control plants. We show that this is due to processes in the plant after JA treatment rather than an effect of JA itself. The oviposition preference for control plants is adaptive, as development time from larval hatch until pupation of P. rapae caterpillars was longer on JA-treated plants. Total glucosinolate content in leaf surface extracts was similar for control and treated plants; however, two of the five glucosinolates were present in lower amounts in leaf surface extracts of JA-treated plants. When the butterflies were offered a choice between the purified glucosinolate fraction isolated from leaf surface extracts of JA-treated plants and that from control plants, they did not discriminate. Changes in leaf surface glucosinolate profile, therefore, do not seem to explain the change in oviposition preference of the butterflies after JA treatment, suggesting that as yet unknown infochemicals are involved

Inheritance analysis and identification of SNP markers associated with ZYMV resistance in Cucurbita pepo

[EN] Cucurbit crops are economically important worldwide. One of the most serious threats to cucurbit production is Zucchini yellow mosaic virus (ZYMV). Several resistant accessions were identified in Cucurbita moschata and their resistance was introgressed into Cucurbita pepo. However, the mode of inheritance of ZYMV resistance in C. pepo presents a great challenge to attempts at introgressing resistance into elite germplasm. The main goal of this work was to analyze the inheritance of ZYMV resistance and to identify markers associated with genes conferring resistance. An Illumina GoldenGate assay allowed us to assess polymorphism among nine squash genotypes and to discover six polymorphic single-nucleotide polymorphisms (SNPs) between two near-isogenic lines, "True French" (susceptible to ZYMV) and Accession 381e (resistant to ZYMV). Two F-2 and three BC1 populations obtained from crossing the ZYMV-resistant Accession 381e with two susceptible ones, the zucchini True French and the cocozelle "San Pasquale," were assayed for ZYMV resistance. Molecular analysis revealed an approximately 90% association between SNP1 and resistance, which was confirmed using High Resolution Melt (HRM) and a CAPS marker. Co-segregation up to 72% in populations segregating for resistance was observed for two other SNP markers that could be potentially linked to genes involved in resistance expression. A functional prediction of proteins involved in the resistance response was performed on genome scaffolds containing the three SNPs of interest. Indeed, 16 full-length pathogen recognition genes (PRGs) were identified around the three SNP markers. In particular, we discovered that two nucleotide-binding site leucine-rich repeat (NBS-LRR) protein-encoding genes were located near the SNP1 marker. 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