Synthesis of Curcumin Derivatives and Analysis of Their Antitumor Effects in Triple Negative Breast Cancer (TNBC) Cell Lines

We analyzed antitumor effects of a series of curcumin analogues. Some of them were obtained by reaction of substitution involving the two phenolic OH groups of curcumin while the analogues with a substituent at C-4 was prepared following an original procedure that regards the condensation of benzenesulfenic acid onto the nucleophilic central carbon of the curcumin skeleton. We analyzed cytotoxic effects of such derivatives on two TNBC (triple negative breast cancer) cell lines, SUM 149 and MDA-MB-231, but only three of them showed an IC50 in a lower micromolar range with respect to curcumin. We also focused on these three derivatives that in both cell lines exhibited a higher or at least equivalent pro-apoptotic effect than curcumin. The analysis of molecular mechanisms of action of the curcumin derivatives under study has highlighted that they decreased NF-κB transcriptional factor activity, and consequently the expression of some NF-κB targets. Our data confirmed once again that curcumin may represent a very good lead compound to design analogues with higher antitumor capacities and able to overcome drug resistance with respect to conventional ones, even in tumors difficult to treat as TNBC

Classical-path integral adaptive resolution in molecular simulation: towards a smooth quantum-classical coupling

Simulations that couple different classical molecular models in an adaptive way by changing the number of degrees of freedom on the fly, are available within reasonably consistent theoretical frameworks. The same does not occur when it comes to classical-quantum adaptivity. The main reason for this is the difficulty in describing a continuous transition between the two different kind of physical principles: probabilistic for the quantum and deterministic for the classical. Here we report the basic principles of an algorithm that allows for a continuous and smooth transition by employing the path integral description of atoms.Comment: 8 pages 4 figure

Essential oil of Cyphostemma juttae (Vitaceae): chemical composition and antitumor mechanism in triple negative breast cancer cells

The genus Cyphostemma (Planch.) Alston (Vitaceae) includes about 150 species distrib- uted in eastern and southern Africa and Madagascar. Some species are used in traditional medicine and their biological activities, including antiproliferative effects against cancer cell lines, have been demonstrated. To date no investigations on Cyphostemma essential oils have been carried out. Essential oils, which play important roles in plant defenses have been demonstrated to be active in the treatment of several human diseases and to enhance bioavability of other drugs. The aim of this paper was to identify the chemical composition of the essential oil of the leaves of Cyphostemma juttae (Dinter & Gilg) Desc. and to verify some biological activities on two triple negative breast cancer cell lines (MDA-MB-231, SUM 149), characterized by the over-expression of the transcription factor NF-κB. In the essential oil, obtained by hydrodistillation and analysed by gas chromatography-mass spectrometry, 39 compounds were detected and with phytol (30%) dominating the chemical composition. C. juttae essential oil reduced cell growth and showed a pro-oxidant activity in both cell lines. Moreover, C. juttae essential oil caused a substantial decrease of NF-κB activation and consequently a significant reduction of some NF-κB target genes. The present study shows for the first time the cytotoxic properties of C. juttae essential oil and highlight its avail- ability to interfere with NF-κB pathway, suggesting a potential therapeutic use in triple nega- tive breast cancers (TNBCs) of this essential oil

NEW VARIETIES OF DURUM WHEAT (TRITICUM DURUM DESF.) IN SICILY: EVALUATION OF GENOTYPE-ENVIRONMENT INTERACTION

Durum wheat (Triticum durum Desf.) is the typical cereal crop in semi-arid Italian environments, and Sicily, is one of the regions of southern Italy where the cultivation of durum wheat is very spread. The thesis was the comparison of 14 genotypes of durum wheat located in 11 locations typical of the Sicilian cropland in the years 2006-2011. The analysis of the results has allowed to study the productive and qualitative behavior of the tested genotypes. In addition, the study of interaction genotype-environment, has allowed to verify the yield stability in quantity and the quality of the grain by the individual genotypes

Long-term Cropping Systems and Tillage Management Effects on Soil Organic Carbon Stock and Steady State Level of C Sequestration Rates in a Semiarid Environment

A calcareous and clayey xeric Chromic Haploxerepts of a long-term (19 years) experimental site in Sicily (Italy) with different land use management and cropping systems were sampled (0-15 cm depth) to study their effect on soil aggregate stability and associated organic carbon (SOC). The experimental site had three tillage managements (no till [NT], dual-layer [DL] and conventional tillage [CT]) and two cropping systems (durum wheat mono-cropping [W] and durum wheat/faba bean rotation [WB]). The whole site covered an area of 4440 m2 with individual plots having 370 m2. The soil was ploughed during the experiment. Samples (2 – 4 kg each) were taken before and after the experiment. The annually sequestered SOC with W was 2.75 times higher than with WB and higher SOC concentrations were measured. The NT management system was the most effective in SOC sequestration whereas with DL no C was sequestered. The differences in SOC concentrations between NT and CT were surprisingly small. Cumulative C input of all cropping and tillage systems and the annually sequestered SOC indicated that a steady state occurred at a sequestration rate of 7.4 Mg C ha-1 yr-1. Independent of the cropping systems, most of the SOC was stored in the silt and clay fraction. This fraction had a high N content which is typical for organic matter interacting strongly with minerals. Macro-aggregates (> 250µm) were influenced by the treatments whereas the finest fractions were not. DL reduced the SOC in macro-aggregates while NT and CT gave rise to much higher SOC contents

Indeterminate Thyroid Nodules: From Cytology to Molecular Testing

Thyroid cancer is the most common malignancy of the endocrine system. Fine-needle aspiration (FNA) biopsy of thyroid nodules has become the gold standard procedure, in terms of cost and efficacy, for guiding clinicians towards appropriate patients’ management. One challenge for cytopathologists is to accurately classify cytological specimens as benign or malignant based on cytomorphological features. In fact, with a frequency ranging from 10% to 30%, nodules are diagnosed as indeterminate. In recent years, the mutational landscape of thyroid tumors has been extensively described, and two molecular profiles have been identified: RAS-like (NRAS, HRAS, and KRAS mutations; EIF1AX mutations; BRAF K601E mutation; and PPARG and THADA fusions) and BRAFV600E-like (including BRAFV600E mutation and RET and BRAF fusions). The purpose of this review is to discuss the latest molecular findings in the context of indeterminate thyroid nodules, highlighting the role of molecular tests in patients’ management

Epigenetic changes and nuclear factor-\u3baB activation, but not microRNA-224, downregulate Raf-1 kinase inhibitor protein in triple\u2011negative breast cancer SUM 159 cells

Raf-1 kinase inhibitor protein (RKIP) is a tumor suppressor and metastasis inhibitor, which enhances drug\u2011induced apoptosis of cancer cells. Downregulation of RKIP may be significant in the biology of highly aggressive and drug\u2011resistant tumors, for example triple\u2011negative breast cancers (TNBCs). Potential causes for the low levels of RKIP expressed by SUM 159 TNBC cells were investigated in the present study. Bisulphite modification, methylation specific\u2011polymerase chain reaction (PCR) and a TransAM NF-\u3baB assay were performed and the results suggested that various mechanisms, including methylation of the gene promoter, histone deacetylation and nuclear factor\u2011\u3baB (NF\u2011\u3baB) activation, but not targeting by microRNA\u2011224 (miR/miRNA\u2011224), as determined by transfection of pre\u2011miR\u2011224 miRNA precursor or anti\u2011miR\u2011224 miRNA inhibitor, may downregulate RKIP in these cells. Furthermore, reverse transcription\u2011quantitative PCR, western blotting,3\u2011(4,5\u2011dimethylthiazol\u20112\u2011yl)\u20115\u2011(3\u2011carboxymethoxyphenyl)\u20112\u2011(4\u2011sulphophenyl)\u20112H\u2011tetrazolium cell growth assay and flow cytometry revealed that in SUM 159 cells, the demethylating agent 5\u2011aza\u20112'\u2011deoxycytidine (5\u2011AZA), the histone deacetylase inhibitor trichostatin A (TSA) and the NF\u2011\u3baB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) enhanced RKIP expression and resulted in significant cell growth inhibition and induction of apoptosis. 5\u2011AZA and TSA mainly produced additive antitumor effects, while the combination of DHMEQ and TSA exhibited significant synergy in cell growth inhibition and induction of apoptosis assays. Increasing evidence that aberrant activation of NF\u2011\u3baB signaling is a frequent characteristic of TNBC highlights the fact that this transcription factor may be a useful target for treatment of such tumors. In addition to DHMEQ, proteasome inhibitors may also represent valuable therapeutic resources in this context. Notably, proteasome inhibitors, in addition to the inhibition of NF\u2011\u3baB activation, may also restore RKIP levels by inhibiting proteasome degradation of the ubiquitinated protein. The current results contribute to the understanding of the molecular mechanisms of RKIP downregulation in TNBC and suggest possible novel therapeutic approaches for the treatment of these types of cancer

Gender Differences in Parental Leave Before and After the Introduction of a Paid Parental Leave Policy: A Sequence Analysis of Administrative Time-Keeping Records

Paid leave confers health benefits to new parents and their children, but the absence of a national paid family leave policy in the United States has left workers to navigate a patchwork of paid and unpaid parental leave benefits accessed through their employers. As public and private paid leave policies expand across the US, it is imperative to determine how these benefits impact leave taking behaviors among new parents. We use sequence and cluster analyses of administrative time-keeping records to detail parental leave-taking during the first 180 days after adding a child among employees of a large public-sector organization with a new paid parental leave policy. Results show that the additional paid leave benefits replaced some of the unpaid leave women were taking and also lengthened their total leave duration. For men, who were only taking paid leave, the additional benefits allowed them to save their sick leave but left total leave duration unaffected. This study highlights the complex ways paid leave policies impact leave-taking among new parents. As more state and municipal governments consider paid family leave policies, understanding the interplay between these policies and existing organizational structures is critical to maximize the benefits across the workplace and limit unintended consequences