Synthesis and structure - Activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines, and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogs of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB- 231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data the SAR study concluded that more than 75% of the open-chain Lam-D analogs tested showed cytotoxicity in a low micromolar GI50 range

Results of an international phosphorus digestibility ring test with broiler chickens

The objective of this ring test was to investigate the prececal phosphorus (P) digestibility of soybean meal (SBM) in broiler chickens using the trial protocol proposed by the World's Poultry Science Association. It was hypothesized that prececal P digestibility of SBM determined in the collaborating stations is similar. Three diets with different inclusion levels of SBM were mixed in a feed mill specialized in experimental diets and transported to 17 collaborating stations. Broiler chicks were raised on commercial starter diets according to station-specific management routine. Then they were fed the experimental diets for a minimum of 5 d before content of the posterior half of the ileum was collected. A minimum of 6 experimental replicates per diet was used in each station. All diets and digesta samples were analyzed in the same laboratory. Diet, station, and their interaction significantly affected (P < 0.05) the prececal digestibility values of P and calcium of the diets. The prececal P digestibility of SBM was determined by linear regression and varied among stations from 19 to 51%, with significant differences among stations. In a subset of 4 stations, the prececal disappearance of myo-inositol 1,2,3,4,5,6-hexakis (dihydrogen phosphate)-P; InsP6-P) also was studied. The prececal InsP6-P disappearance correlated well with the prececal P digestibility. We hypothesized that factors influencing InsP6 hydrolysis were main contributors to the variation in prececal P digestibility among stations. These factors were probably related to the feeding and housing conditions (floor pens or cages) of the birds in the pre-experimental phase. Therefore, we suggest that the World's Poultry Science Association protocol for the determination of digestible P be should extended to the standardization of the pre-experimental period. We also suggest that comparisons of P digestibility measurements among studies are made only with great caution until the protocol is more refined

PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer

Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan–PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death

Respuesta a la selección por caracteres reproductivos en poblaciones de gallinas catalanas

Resumen de la comunicación presentada al III Congreso Ibérico sobre Recursos Genéticos Animale