Thoracic X-Strap Harness. Design and Method 2

No abstract

Monitoring the dynamics of Src activity in response to anti-invasive dasatinib treatment at a subcellular level using dual intravital imaging

Optimising response to tyrosine kinase inhibitors in cancer remains an extensive field of research. Intravital imaging is an emerging tool, which can be used in drug discovery to facilitate and fine-tune maximum drug response in live tumors. A greater understanding of intratumoural delivery and pharmacodynamics of a drug can be obtained by imaging drug target-specific fluorescence resonance energy transfer (FRET) biosensors in real time. Here, we outline our recent work using a Src-FRET biosensor as a readout of Src activity to gauge optimal tyrosine kinase inhibition in response to dasatinib treatment regimens in vivo. By simultaneously monitoring both the inhibition of Src using FRET imaging, and the modulation of the surrounding extracellular matrix using second harmonic generation (SHG) imaging, we were able to show enhanced drug penetrance and delivery to live pancreatic tumors. We discuss the implications of this dual intravital imaging approach in the context of altered tumor-stromal interactions, while summarising how this approach could be applied to assess other combination strategies or tyrosine kinase inhibitors in a preclinical setting

RUNX-mediated growth arrest and senescence are attenuated by diverse mechanisms in cells expressing RUNX1 fusion oncoproteins

RUNX gene over-expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX-mediated growth suppression? Previous studies showed that the TEL-RUNX1 fusion from t(12;21) B-ALLs is unable to induce senescence-like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1-ETO fusion found in t(8;21) AMLs. We now show that SLGA potential is suppressed in TEL-RUNX1 but reactivated by deletion of the TEL HLH domain or mutation of a key residue (K99R). Attenuation of SLGA activity is also a feature of RUNX1-ETO9a, a minor product of t(8;21) translocations with increased leukemogenicity. Finally, while RUNX1-ETO induces SLGA it also drives a potent senescence-associated secretory phenotype (SASP), and promotes the immortalisation of rare cells that escape SLGA. Moreover, the RUNX1-ETO SASP is not strictly linked to growth arrest as it is largely suppressed by RUNX1 and partially activated by RUNX1-ETO9a. These findings underline the heterogeneous nature of premature senescence and the multiple mechanisms by which this failsafe process is subverted in cells expressing RUNX1 oncoproteins

Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation

Mesenchymal cell motility is driven by polarized actin polymerization [1]. Signals at the leading edge recruit actin polymerization machinery to promote membrane protrusion, while matrix adhesion generates tractive force to propel forward movement. To work effectively, cell motility is regulated by a complex network of signaling events that affect protein activity and localization. H2O2 has an important role as a diffusible second messenger [2], and mediates its effects through oxidation of cysteine thiols. One cell activity influenced by H2O2 is motility [3]. However, a lack of sensitive and H2O2-specific probes for measurements in live cells has not allowed for direct observation of H2O2 accumulation in migrating cells or protrusions. In addition, the identities of proteins oxidized by H2O2 that contribute to actin dynamics and cell motility have not been characterized. We now show, as determined by fluorescence lifetime imaging microscopy, that motile cells generate H2O2 at membranes and cell protrusions and that H2O2 inhibits cofilin activity through oxidation of cysteines 139 (C139) and 147 (C147). Molecular modeling suggests that C139 oxidation would sterically hinder actin association, while the increased negative charge of oxidized C147 would lead to electrostatic repulsion of the opposite negatively charged surface. Expression of oxidation-resistant cofilin impairs cell spreading, adhesion, and directional migration. These findings indicate that H2O2 production contributes to polarized cell motility through localized cofilin inhibition and that there are additional proteins oxidized during cell migration that might have similar roles

The ocean change : management patterns and the environment

Since the 1960s, the rapid development of the international Law of the Sea has outstripped the capacity of most maritime states for developing and implementing policy. The delimitation of the Exclusive Economic Zone (EEZ), which resulted from the United Nations’ Convention on the Law of the Sea (1982) brought about an extension of its area, within which the sate exercise control over all resources and economic activities. At the same time as the jurisdiction of the state has encroached seawards, there has been a significant increase in the range of opportunities for the use of the offshore zone. Until now, the most common approach to managing Malta's marine and coastal resources has been to regulate activities. Thus, regulations concerning constructions on the foreshore, transport of sand, recreational activities on the coast, commercial fishing, control of pollution, shipping and other related marine activities exist. These regulations are not sufficient to safeguard marine resources or to ensure maximal sustainable use. Some regulations are outdated, others are not enforced and different sets of regulations may actually conflict. This situation is not unique to the coastal zone, but it is also true for the whole island. In general, Malta's development has been haphazard and piecemeal and not regulated by any national plan, formulated on the basis of a scientific study of the country's physical, economic, social and cultural characteristics, existing and projected needs and the necessity for maintaining environmental quality. Recognizing this, the Maltese government is in the process of drafting national planning guidelines in the form of the Malta Structure Plan. As a first step towards fulfilling this objective, the Planning Services Division of the Ministry for Development of Infra- structure commissioned a Coastal Zone Survey of the Maltese Islands. As part of this, a survey of the terrestrial part of the coastal zone was carried out over a six-week period from early July 1989 by a joint team from the Universities of Durham and Malta. The output of this survey comprised a report of the survey, coastal land-use maps on a scale of 1:2,500, a series of synoptic land-use maps on a scale of 1:25,000, and a series of synoptic maps on various scales, depicting coastal features of ecologjcal importance. This in the hope of determining which areas are to be preserved and which are to be used for economic gain.peer-reviewe

Disturbed Fossil Group Galaxy NGC 1132

We have analyzed the Chandra archival data of NGC 1132, a well-known fossil group, i.e. a system expected to be old and relaxed long after the giant elliptical galaxy assembly. Instead, the Chandra data reveal that the hot gas morphology is disturbed and asymmetrical, with a cold front following a possible bow shock. We discuss possible origins of the disturbed hot halo, including sloshing by a nearby object, merger, ram pressure by external hotter gas and nuclear outburst. We consider that the first two mechanisms are likely explanations for the disturbed hot halo, with a slight preference for a minor merger with a low impact parameter because of the match with simulations and previous optical observations. In this case, NGC 1132 may be a rare example of unusual late mergers seen in recent simulations. Regardless of the origin of the disturbed hot halo, the paradigm of the fossil system needs to be reconsidered.Comment: 16 pages, 6 figures, accepted for publication in Ap