Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.

Orosomucoid (alpha-1 acid glycoprotein) phenotyping by use of immobilized pH gradients with 8 M urea and immunoblotting. A new variant encountered in a population study.

Orosomucoid (ORM) phenotyping has been performed on 329 unrelated Swiss subjects, using immobilized pH gradients with 8 M urea and 2% v/v 2-mercaptoethanol followed by immunoblotting. After desialylation the band patterns of ORM confirmed that the polymorphism of the structural locus ORM1 is controlled by three codominant autosomal alleles (ORM1*F1, ORM1*S and ORM1*F2). One rare and one new allele were detected. The rare variant, tentatively assigned to the second structural locus ORM2, is observed in a cathodal position and named ORM2 B1. The new variant, tentatively assigned to the first structural locus ORM1, is observed in a region located between ORM1 S and ORM1 F2, and named ORM1 F3. Moreover, the pI values of the ORM variants have been measured accurately with Immobiline Dry Plates (LKB): they were found to be within the pH range 4.93-5.14.

Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey.

BACKGROUND: Predicting outcome of breast cancer (BC) patients based on sentinel lymph node (SLN) status without axillary lymph node dissection (ALND) is an area of uncertainty. It influences the decision-making for regional nodal irradiation (RNI). The aim of the NORA (NOdal RAdiotherapy) survey was to examine the patterns of RNI. METHODS: A web-questionnaire, including several clinical scenarios, was distributed to 88 EORTC-affiliated centers. Responses were received between July 2013 and January 2014. RESULTS: A total of 84 responses were analyzed. While three-dimensional (3D) radiotherapy (RT) planning is carried out in 81 (96%) centers, nodal areas are delineated in only 51 (61%) centers. Only 14 (17%) centers routinely link internal mammary chain (IMC) and supraclavicular node (SCN) RT indications. In patients undergoing total mastectomy (TM) with ALND, SCN-RT is recommend by 5 (6%), 53 (63%) and 51 (61%) centers for patients with pN0(i+), pN(mi) and pN1, respectively. Extra-capsular extension (ECE) is the main factor influencing decision-making RNI after breast conserving surgery (BCS) and TM. After primary systemic therapy (PST), 49 (58%) centers take into account nodal fibrotic changes in ypN0 patients for RNI indications. In ypN0 patients with inner/central tumors, 23 (27%) centers indicate SCN-RT and IMC-RT. In ypN1 patients, SCN-RT is delivered by less than half of the centers in patients with ypN(i+) and ypN(mi). Twenty-one (25%) of the centers recommend ALN-RT in patients with ypN(mi) or 1-2N+ after ALND. Seventy-five (90%) centers state that age is not considered a limiting factor for RNI. CONCLUSION: The NORA survey is unique in evaluating the impact of SLNB/ALND status on adjuvant RNI decision-making and volumes after BCS/TM with or without PST. ALN-RT is often indicated in pN1 patients, particularly in the case of ECE. Besides the ongoing NSABP-B51/RTOG and ALLIANCE trials, NORA could help to design future specific RNI trials in the SLNB era without ALND in patients receiving or not PST.

Simultaneous irradiation of fibroblasts and carcinoma cells repress the secretion of soluble factors able to stimulate carcinoma cell migration.

Stroma mediated wound healing signals may share similarities with the ones produced by tumor's microenvironment and their modulation may impact tumor response to the various anti-cancer treatments including radiation therapy. Therefore we conducted this study, to assess the crosstalk between stromal and carcinoma cells in response to radiotherapy by genetic modulation of the stroma and irradiation. We found that fibroblasts irrespective of their RhoB status do not modulate intrinsic radiosensitivity of TC-1 but produce diffusible factors able to modify tumor cell fate. Then we found that Wt and RhoB deficient fibroblasts stimulated TC-1 migration through distinct mechanisms which are TGF-β1 and MMP-mediated respectively. Lastly, we found that simultaneous irradiation of fibroblasts and TC-1 abrogated the pro-migratory phenotype by repression of TGF-β and MMP secretion. This last result is highly relevant to the clinical situation and suggests that conversely to, the current view; irradiated stroma would not enhance carcinoma migration and could be manipulated to promote anti-tumor immune response.