Resistance mechanisms to cancer chemotherapy

Resistance to chemotherapy ('drug resistance') is a fundamental problem that limits the effectiveness of many chemotherapies currently used to treat cancer. Drug resistance can occur due to a variety of mechanisms, such as increased drug inactivation, drug efflux from cancer cells, enhanced repair of chemotherapy-induced damage, activation of pro-survival pathways and inactivation of cell death pathways. In this article, we review some of the major mechanisms of drug resistance and discuss how new molecularly-targeted therapies are being increasingly used to overcome these resistance mechanisms.

HOX genes: seductive science, mysterious mechanisms

HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21 [corrected] 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network.

Mechanisms and chemistry of dye adsorption on manganese oxides-modified diatomite

The investigations into structural changes which occur during adsorbent modification and the adsorption mechanisms are essential for an effective design of adsorption systems. Manganese oxides were impregnated onto diatomite to form the type known as delta-birnessite. Initial investigations established the effectiveness of manganese oxides-modified diatomite (MOMD) to remove basic and reactive dyes from aqueous solution. The adsorption capacity of MOMD for methylene blue (MB), hydrolysed reactive black (RB) and hydrolysed reactive yellow (RY) was 320, 419, and 204 mg/g, respectively. Various analytical techniques were used to characterise the structure and the mechanisms of the dye adsorption process onto MOMD such as Fourier transform infrared (FTIR), X-ray diffraction (XRD) and atomic absorption spectrometry (A.A.). A small shift to higher values of the cl-spacing of dye/MOMD was observed indicating that a small amount of the dye molecules were intercalated in the MOMD structure and other molecules were adsorbed on the external surface of MOMD. Two mechanisms of dye adsorption onto MOMD were proposed; intercalation of the dye in the octahedral layers and adsorption of the dye on the MOMD external surface. Moreover, the results demonstrated that the MOMD structure was changed upon insertion of MB and RY with an obvious decrease in the intensity of the second main peak of the MOMD X-ray pattern. (C) 2009 Elsevier Ltd. All rights reserved.

Monkey and humans exhibit similar motion-processing mechanisms

Single cell recording studies have resulted in a detailed understanding of motion-sensitive neurons in non-human primate visual cortex. However, it is not known to what extent response properties of motion-sensitive neurons in the non-human primate brain mirror response characteristics of motion-sensitive neurons in the human brain. Using a motion adaptation paradigm, the direction aftereffect, we show that changes in the activity of human motion-sensitive neurons to moving dot patterns that differ in dot density bear a strong resemblance to data from macaque monkey. We also show a division-like inhibition between neural populations tuned to opposite directions, which also mirrors neural-inhibitory behaviour in macaque. These findings strongly suggest that motion-sensitive neurons in human and non-human primates share common response and inhibitory characteristics.

The story of some: Everyday pragmatic inference by children and adults

The statement, some elephants have trunks, is logically true but pragmatically infelicitous. Whilst some is logically consistent with all, it is often pragmatically interpreted as precluding all. In Experiments 1 and 2, we show that with pragmatically impoverished materials, sensitivity to the pragmatic implicature associated with some is apparent earlier in development than has previously been found. Amongst 8-year-old children, we observed much greater sensitivity to the implicature in pragmatically enriched contexts. Finally, in Experiment 3, we found that amongst adults, logical responses to infelicitous some statements take longer to produce than do logical responses to felicitous some statements, and that working memory capacity predicts the tendency to give logical responses to the former kind of statement. These results suggest that some adults develop the ability to inhibit a pragmatic response in favour of a logical answer. We discuss the implications of these findings for theories of pragmatic inference.

The suppression of q card selections: Evidence for deductive inference in Wason's Selection Task

The results of three experiments investigating the role of deductive inference in Wason's selection task are reported. In Experiment 1, participants received either a standard one-rule problem or a task containing a second rule, which specified an alternative antecedent. Both groups of participants were asked to select those cards that they considered were necessary to test whether the rule common to both problems was true or false. The results showed a significant suppression of q card selections in the two-rule condition. In addition there was weak evidence for both decreased p selection and increased not-q selection. In Experiment 2 we again manipulated number of rules and found suppression of q card selections only. Finally, in Experiment 3 we compared one- and two-rule conditions with a two-rule condition where the second rule specified two alternative antecedents in the form of a disjunction. The q card selections were suppressed in both of the two-rule conditions but there was no effect of whether the second rule contained one or two alternative antecedents. We argue that our results support the claim that people make inferences about the unseen side of the cards when engaging with the indicative selection task.