Dasatinib Inhibits CXCR4 Signaling in Chronic Lymphocytic Leukaemia Cells and Impairs Migration Towards CXCL12

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its'' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies.     

Gender Differentiated Preferences for a Community-Based Conservation Initiative

Community-based conservation (CBC) aims to benefit local people as well as to achieve conservation goals, but has been criticised for taking a simplistic view of “community” and failing to recognise differences in the preferences and motivations of community members. We explore this heterogeneity in the context of Kenya’s conservancies, focussing on the livelihood preferences of men and women living adjacent to the Maasai Mara National Reserve. Using a discrete choice experiment we quantify the preferences of local community members for key components of their livelihoods and conservancy design, differentiating between men and women and existing conservancy members and non-members. While Maasai preference for pastoralism remains strong, non-livestock-based livelihood activities are also highly valued and there was substantial differentiation in preferences between individuals. Involvement with conservancies was generally perceived to be positive, but only if households were able to retain some land for other purposes. Women placed greater value on conservancy membership, but substantially less value on wage income, while existing conservancy members valued both conservancy membership and livestock more highly than did non-members. Our findings suggest that conservancies can make a positive contribution to livelihoods, but care must be taken to ensure that they do not unintentionally disadvantage any groups. We argue that conservation should pay greater attention to individual-level differences in preferences when designing interventions in order to achieve fairer and more sustainable outcomes for members of local communities.     

From Regional to National Clouds: TV Coverage in the Czech Republic

Media, and particularly TV media, have a great impact on the general public. In recent years, spatial patterns of information and the relevance of intangible geographies have become increasingly important. Gatekeeping plays a critical role in the selection of information that is transformed into media. Therefore, gatekeeping, through national media, also co-forms the generation of mental maps. In this paper, correspondence analysis (a statistical method) combined with cloud lines (a new visual analytics technique) is used to analyze how individual major regional events in one of the post-communist countries, the Czech Republic, penetrate into the media on a national scale. Although national news should minimize distortions about regions, this assumption has not been verified by our research. Impressions presented by the media of selected regions that were markedly influenced by one or several events in those regions demonstrate that gatekeepers, especially news reporters, functioned as a filter by selecting only a few specific, and in many cases, unusual events for dissemination.     

Survival of Escherichia coli in the environment: fundamental and public health aspects

In this review, our current understanding of the species Escherichia coli and its persistence in the open environment is examined. E. coli consists of six different subgroups, which are separable by genomic analyses. Strains within each subgroup occupy various ecological niches, and can be broadly characterized by either commensalistic or different pathogenic behaviour. In relevant cases, genomic islands can be pinpointed that underpin the behaviour. Thus, genomic islands of, on the one hand, broad environmental significance, and, on the other hand, virulence, are highlighted in the context of E. coli survival in its niches. A focus is further placed on experimental studies on the survival of the different types of E. coli in soil, manure and water. Overall, the data suggest that E. coli can persist, for varying periods of time, in such terrestrial and aquatic habitats. In particular, the considerable persistence of the pathogenic E. coli O157:H7 is of importance, as its acid tolerance may be expected to confer a fitness asset in the more acidic environments. In this context, the extent to which E. coli interacts with its human/animal host and the organism''s survivability in natural environments are compared. In addition, the effect of the diversity and community structure of the indigenous microbiota on the fate of invading E. coli populations in the open environment is discussed. Such a relationship is of importance to our knowledge of both public and environmental health.     

Effect of a sudden and a slow concentration increase in plasma urea on its concentration in some tissues of the dog and rat

The urea concentration in the renal cortex ([RC]) of pentobarbital-anaesthetized dogs was 5.71 times higher than the plasma concentration ([P]); the liver ([L]) and the skeletal muscle ([SM]) concentrations were the same as ([P]). Rapid infusion of 20% urea (1 g/kg b.w. within 1 min) was followed by a sudden increase in [P]; [RC] and [L] rose to values nonsignificantly different from [P] and remained non-significantly different for the whole 4 hours of the experiment; at the end, [P] was still about 10 times higher than before infusion. Surprisingly, [SM] 2 and 6 min after infusion was significantly lower than [P]; later they were the same. The experiment thus does not testify to the existence of active transport of urea in the RC. The permeability of the skeletal muscle membrane for urea is lower than that of the RC and liver. Chronic uraemia was induced in rats by transplanting the trigonum vesicae into the peritoneal cavity. In addition to the chemical determination of urea, 14C-urea (marked*) was also measured. [RC]/[P] and [RC*]/[P*] fell as [P] rose; [L], [L*] [SM] and [SM*] never differed from [P] or [P*]. Fluid [PF] collected in the peritoneal cavity had the same chemically determined and radioactive urea concentration as P, but it was hypoosmolar and had a lower [Na+] than P. These experiments likewise did not testify to active urea transport in the RC. It is not clear what caused the osmolarity and sodium gradient between the PF and P, but the peritoneal wall definitely did not act as a simple dialyzing membrane.     

Assessing the Effect of the Best Treatment. A Non-parametric Inference Problem

For patients of a certain type, a number of treatments are available. The effect of each such treatment is assumed to be described by a shift model; it is, however, admitted that there may be an interaction between patient and treatment, meaning in particular that the treatment which is best for one patient is not necessarily best for another. The problem is the following: if each patient is given the treatment which is optimal for that particular patient, will this produce a significant effect and, if so, how large is the effect?