No abstract

Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.

No abstract

No abstract

We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41.

In 60 patients undergoing inguinal hernia repair, we compared the clinical profile of unilateral spinal anesthesia produced with either 8 mg of hyperbaric bupivacaine 0.5% (n = 20), 8 mg of hyperbaric levobupivacaine 0.5% (n = 20), or 12 mg of hyperbaric ropivacaine 0.5% (n = 20). The study drug was injected slowly through a 25-gauge Whitacre directional needle and patients maintained the lateral decubitus position for 15 min. The onset time and intraoperative efficacy were similar in the three groups. The maximal level of sensory block on the operative and nonoperative sides was T6 (T12-5) and L3 (/[no sensory level detectable]-T4) with bupivacaine, T8 (T12-5) and L3 (/-T3) with levobupivacaine, T5 (T10-2) and T11 (/-T3) with ropivacaine (P = 0.11, P = 0.23, respectively). Complete regression of spinal anesthesia occurred after 166 +/- 42 min with ropivacaine, 210 +/- 63 min with levobupivacaine, and 190 +/- 51 min with bupivacaine (P = 0.03 and P = 0.04, respectively); however, no differences were observed in time for home discharge (329 +/- 89 min with bupivacaine, 261 +/- 112 min with levobupivacaine, and 332 +/- 57 min with ropivacaine [P = 0.28]). We conclude that 8 mg of levobupivacaine or 12 mg of ropivacaine are acceptable alternatives to 8 mg of bupivacaine when limiting spinal block at the operative side for inguinal hernia repair.

Evolutionary change results from selection acting on genetic variation. For migration to be successful, many different aspects of an animal's physiology and behaviour need to function in a co-coordinated way. Changes in one migratory trait are therefore likely to be accompanied by changes in other migratory and lifehistory traits. At present, we have some knowledge of the pressures that operate at the various stages of migration, but we know very little about the extent of genetic variation in various aspects of the migratory syndrome. As a consequence, our ability to predict which species is capable of what kind of evolutionary change, and at which rate, is limited. Here, we review how our evolutionary understanding of migration may benefit from taking a quantitative-genetic approach and present a framework for studying the causes of phenotypic variation. We review past research, that has mainly studied single migratory traits in captive birds, and discuss how this work could be extended to study genetic variation in the wild and to account for genetic correlations and correlated selection. In the future, reactionnorm approaches may become very important, as they allow the study of genetic and environmental effects on phenotypic expression within a single framework, as well as of their interactions. We advocate making more use of repeated measurements on single individuals to study the causes of among-individual variation in the wild, as they are easier to obtain than data on relatives and can provide valuable information for identifying and selecting traits. This approach will be particularly informative if it involves systematic testing of individuals under different environmental conditions. We propose extending this research agenda by using optimality models to predict levels of variation and covariation among traits and constraints. This may help us to select traits in which we might expect genetic variation, and to identify the most informative environmental axes. We also recommend an expansion of the passerine model, as this model does not apply to birds, like geese, where cultural transmission of spatio-temporal information is an important determinant of migration patterns and their variation.

No abstract