Conformational Assignement, Absolute Configuration and Chiral Separation of all the Stereoisomers Created by the Combined Presence of Stereogenic Centers and Stereogenic Conformational Axes in a Highly Hindered 1,5-Naphthyl Sulfoxide.

The presence of two stereogenic centers and of two stereogenic conformational axes in 2,6-dimethyl-1,5-bis(2-methyl-2-propylsulfinyl)naphthalene (1) entails the existence of 10 stereoisomers. In particular, both the meso form (1a) and the racemic form (1b) are constituted by three atropisomers; in the case of the latter (1b) each of them entails a pair of enantiomers (total of six species), whereas owing to the symmetry only one of the three atropisomers of the meso form (1a) yields a pair of enantiomers (a total of four species). Despite the low conformational interconversion barrier (18.5 kcal/mol) all of them have been separated by low temperature (-45°C) chiral HPLC. Their configurational and conformational assignment has been achieved by a combined use of NMR (both in solution and solid state) and on-line CD-detected chiral HPLC. The single crystal X-ray diffraction yielded the absolute configuration of one of the stereoisomers ((ZR,ER)-1b) from which all the others could be obtained by CD relationship

2,12-diaza[6]helicene: An efficient non-conventional stereogenic scaffold for enantioselective electrochemical interphases

The new configurationally stable, unsymmetrical 2,12-diaza[6]helicene was synthesized as a racemate and the enantiomers were separated in an enantiopure state by semi-preparative HPLC on chiral stationary phase. Under selected alkylation conditions it was possible to obtain both the enantiopure 2-N-mono- and di-N-ethyl quaternary iodides. Metathesis with bis(trifluoromethanesulfonyl)imide anion gave low-melting salts which were tested as inherently chiral additives to achiral ionic liquids for the electrochemical enantiodiscrimination of chiral organic probes in voltammetric experiments. Remarkable differences in the oxidation potentials of the enantiomers of two probes, a chiral ferrocenyl amine and an aminoacid, were achieved; the differences increase with increasing additive concentration and number of alkylated nitrogen atoms

Increased incidence of breast cancer in postmenopausal women with high body mass index at the modena screening program

Purpose: We conducted a study to evaluate the relationship between body mass index (BMI) and the risk of breast cancer (BC) and outcome in a population of 14,684 women aged 55 to 69 years eligible to participate in the Mammography Screening Program (MSP) in the Province of Modena, Italy. Methods: The study population was drawn from women who underwent mammography screening between 2004 and 2006 in the Province of Modena. Women were subdivided into obese, overweight, and normal-weight categories according to BMI and followed until July 31, 2010, to evaluate the BC incidence. The clinicopathological characteristics of BC were also evaluated in different groups of patients classified according to BMI. After BC diagnosis, patients were followed for a median period of 65 (range, 2\u2013104) months. Second events (recurrences and second tumors) were recorded, and the 5-year event-free survival (EFS) was calculated. Results: After a period of 73 months, 366 cases of BC were diagnosed. Compared with normal-weight women, obese women had a significantly higher incidence of BC (relative risk [RR], 1.32; p= 0.040) (RR=1), larger tumors (27% of tumors were larger than T2 size), and more nodal involvement (38.5% of tumors were node-positive). Furthermore, a significantly higher rate of total events was seen in obese women compared with overweight and normal-weight patients, respectively (17.9% vs. 11.4% vs. 10.8%, p=0.032). The 5-year EFS was 89.0%, 89.0%, and 80.0% for normal-weight, overweight, and obese patients, respectively. Conclusion: We observed a significantly higher risk of BC in obese women among those eligible to participate in the MSP in the Province of Modena. Finally, obese women had more second events and poorer EFS compared to nono bese women

EpiHRMAssay, in tube and in silico combined approach for the scanning and epityping of heterogeneous DNA methylation

Reliable and cost-effective assays with adequate sensitivity are required to detect the DNA methylation profile in plants for scientific and industrial purposes. The proposed novel assay, named EpiHRMAssay, allows to quantify the overall methylation status at target loci and to enable high-throughput analyses. It combines in tube High Resolution Melting Analysis on bisulphite-treated templates with the in silico prediction of the melting profile of virtual epialleles using uMELTSM software. The predicted melting temperatures (Tm-s) of a set of epialleles characterized by different numbers of methylated cytosines (#mC) or different mC configurations were obtained and used to build calibration models, enabling the quantification of methylation in unknown samples using only the in tube observed melting temperature (Tm-o). EpiHRMAssay was validated by analysing the promoter region of CMT3, DDM1, and ROS1 genes involved in the regulation of methylation/demethylation processes and chromatin remodelling within a population of peach plants. Results demonstrate that EpiHRMAssay is a sensitive and reliable tool for locus-specific large-scale research and diagnostic contexts of the regulative regions of genes, in a broad range of organisms, including mammals. EpiHRMAssay also provides complementary information for the assessment of heterogeneous methylation and can address an array of biological questions on epigenetic regulation for diversity studies and for large-scale functional genomics

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients' derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients' monocytes killing of A. fumigatus. CF patients' monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes

Evolution of Early Equus in Italy, Georgia, the Indian Subcontinent, East Africa, and the Origins of African Zebras

We report here ecological and morphological characterization of the main Old World Equus in North America, Asia, Europe, and Africa, by comparing the studied fossil forms with the living Equus grevyi zebra. Equus simplicidens from North America, Equus livenzovenzis, Equus stenonis, and Equus stehlini from Italy, Equus sivalensis from India, Equus cf. stenonis and a small Equus from Georgia (Caucasus), Equus oldowayensis, Equus koobiforensis, and Equus cf. tabeti from Kenya and the extant Equus grevyi are described in their cranial and dental features and are compared in morphological postcranial dimensions by means of log10 ratio analysis. The occurrence of the two horses at the Dmanisi Homo site in Georgia is reported here for the first time. Our comparative analyses allow to confirm the primitive lineage of the ancient zebras as derived from Equus simplicidens, and the successive evolution of the stenonine horses in Asia, South Asia, and Europe during the Plio—Pleistocene. The morphological analysis has reveals a clear trend in third metacarpals and third metatarsals of E. simpicidens, the small Equus from Dmanisi and E. grevyi, suggesting a close relationship between these species. The trend of the stenonine Equus from Europe and Asia confirms the possible derivation from the North America Equus simplicidens. The description of all the Old World Equus is integrated with an overview of their paleoecological context, with a referred section for each locality where these fossils were found. This contribution represents a comprehensive review of the present knowledge of the Old World Equus evolutionary history, with some new important data in deciphering the deep origin and evolution of ancient and living zebras

How many chronic myeloid leukemia patients who started a frontline second-generation tyrosine kinase inhibitor have to switch to a second-line treatment? A retrospective analysis from the monitoring registries of the italian medicines agency (AIFA)

The frequency of patients who switch to a second-line therapy from a frontline second-generation (2gen) tyrosine kinase inhibitor (TKI) such as dasatinib and nilotinib, is still substantially unknown. We retrospectively investigated a large series of chronic phase chronic myeloid leukemia (CP-CML) patients initially treated with 2gen TKIs monitored through the Italian Medicines Agency (AIFA Agenzia Italiana del farmaco) registries. Overall, 2420 patients were analyzed over a period of 6 years. One hundred and fifty-seven patients (16.3%) treated with dasatinib and 164 treated with nilotinib (11.3%) have switched to another drug, with an overall frequency of 13.2%. In the dasatinib cohort, 39.4% of patients changed treatment for failure and 36.3% for intolerance as compared to 45.7% and 27.4% respectively in the nilotinib cohort. Overall, the median time to switch due to resistance was 293 days, whereas it was 317 days in case of intolerance. Resistance was observed mainly in younger male patients with high-risk features, while intolerance was not related to any baseline parameter. After resistance/intolerance to nilotinib, the majority of patients switched to dasatinib (53.8%) whereas in case of frontline dasatinib to ponatinib (43.2%). To the best of our knowledge these data provide the first report on the frequency of discontinuation of frontline 2gen TKIs and on the main causes and pattern of choice to a second-line therapy in the real-life setting