CD33 reponses are blocked by SOCS3 through accelerated proteasomal-mediated turnover

CD33 is a member of the sialic acid–binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML). CD33 contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), which can recruit SHP-1 and SHP-2. How CD33 expression is regulated is unclear. Suppressor of cytokine signaling 3 (SOCS3) is expressed in response to cytokines, LPS, and other PAMPs, and competes with SHP-1/2 binding to ITIMs of cytokine receptors, thereby inhibiting signaling. In this study, using peptide pull-down experiments, we found that SOCS3 can specifically bind to the phosphorylated ITIM of CD33. Additionally, following cross-linking SOCS3 can recruit the ECS E3 ligase resulting in accelerated proteasomal degradation of both CD33 and SOCS3. Our data suggest that the tyrosine motifs in CD33 are not important for internalization, while they are required for degradation. Moreover, SOCS3 inhibited the CD33-induced block on cytokine-induced proliferation. This is the first receptor shown to be degraded by SOCS3 and where SOCS3 and its target protein are degraded concomitantly. Our findings clearly suggest that during an inflammatory response, the inhibitory receptor CD33 is lost by this mechanism. Moreover, this has important clinical implications as tumors expressing SOCS3 may be refractory to -CD33 therapy.

Situation Background Assessment Recommendation (SBAR): Undergraduate Perspectives

Situation Background Assessment and Recommendation (SBAR): Undergraduate Perspectives C Morgan, L Adams, J Murray, R Dunlop, IK Walsh. Ian K Walsh, Centre for Medical Education, Queen’s University Belfast, Mulhouse Building, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6DP Background and Purpose: Structured communication tools are used to improve team communication quality.1,2 The Situation Background Assessment and Recommendation (SBAR) tool is widely adopted within patient safety.3 SBAR effectiveness is reportedly equivocal, suggesting use is not sustained beyond initial training.4-6 Understanding perspectives of those using SBAR may further improve clinical communication. We investigated senior medical undergraduate perspectives on SBAR, particularly when communicating with senior colleagues. Methodology: Mixed methods data collection was used. A previously piloted questionnaire with 12 five point Lickert scale questions and 3 open questions was given to all final year medical students. A subgroup also participated in 10 focus groups, deploying strictly structured audio-recorded questions. Selection was by convenience sampling, data gathered by open text questions and comments transcribed verbatim. In-vivo coding (iterative, towards data saturation) preceded thematic analysis. Results: 233 of 255 students (91%) completed the survey. 1. There were clearly contradictory viewpoints on SBAR usage. A recurrent theme was a desire for formal feedback and a relative lack of practice/experience with SBAR. 2. Students reported SBAR as having variable interpretation between individuals; limiting use as a shared mental model. 3. Brief training sessions are insufficient to embed the tool. 4. Most students reported SBAR helping effective communication, especially by providing structure in stressful situations. 5. Only 18.5% of students felt an alternative resource might be needed. Sub analysis of the themes highlighted: A. Lack of clarity regarding what information to include and information placement within the acronym, B. Senior colleague negative response to SBAR C. Lack of conciseness with the tool. Discussion and Conclusions: Despite a wide range of contradictory interpretation of SBAR utility, most students wish to retain the resource. More practice opportunities/feedback may enhance user confidence and understanding. References: (1) Leonard M, Graham S, Bonacum D. The human factor: the critical importance of effective teamwork and communication in providing safe care. Quality & Safety in Health Care 2004 Oct;13(Suppl 1):85-90. (2) d'Agincourt-Canning LG, Kissoon N, Singal M, Pitfield AF. Culture, communication and safety: lessons from the airline industry. Indian J Pediatr 2011 Jun;78(6):703-708. (3) Dunsford J. Structured communication: improving patient safety with SBAR. Nurs Womens Health 2009 Oct;13(5):384-390. (4) Compton J, Copeland K, Flanders S, Cassity C, Spetman M, Xiao Y, et al. Implementing SBAR across a large multihospital health system. Jt Comm J Qual Patient Saf 2012 Jun;38(6):261-268. (5) Ludikhuize J, de Jonge E, Goossens A. Measuring adherence among nurses one year after training in applying the Modified Early Warning Score and Situation-Background-Assessment-Recommendation instruments. Resuscitation 2011 Nov;82(11):1428-1433. (6) Cunningham NJ, Weiland TJ, van Dijk J, Paddle P, Shilkofski N, Cunningham NY. Telephone referrals by junior doctors: a randomised controlled trial assessing the impact of SBAR in a simulated setting. Postgrad Med J 2012 Nov;88(1045):619-626.

Dublin 1916: theatre of revolt

In his essay, Anti-Object, Kengo Kuma proposes that architecture cannot and should not be understood as object alone but instead always as series of networks and connections, relationships within space and through form. Some of these relationships are tangible, others are invisible. Stan Allen and James Corner have also called for an architecture that is more performative and operative – ‘less concerned with what buildings look like and more concerned with what they do’ – as means of effecting a more intimate and promiscuous relationship between infrastructure, urbanism and buildings. According to Allen this expanding filed offers a reclamation of some of the areas ceded by architecture following disciplinary specialization:

‘Territory, communication and speed are properly infrastructural problems and architecture as a discipline has developed specific technical means to deal with these variables. Mapping, projection, calculation, notation and visualization are among architecture’s traditional tools for operating at the very large scale’.

The motorway may not look like it – partly because we are no longer accustomed to think about it as such – but it is a site for and of architecture, a territory where architecture can be critical and active. If the limits of the discipline have narrowed, then one of the functions of a school of architecture must be an attempt occupy those areas of the built environment where architecture is no longer, or has yet to reach. If this is a project about reclamation of a landscape, it is also a challenge to some of the boundaries that surround architecture and often confine it, as Kuma suggests, to the appreciation of isolated objects.

M:NI 2014-15
We tend to think of the motorway as a thing or an object, something that has a singular function. Historically this is how it has been seen, with engineers designing bridges and embankments and suchlike with zeal … These objects like the M3 Urban Motorway, Belfast’s own Westway, are beautiful of course, but they have caused considerable damage to the city they were inflicted upon.

Actually, it’s the fact that we have seen the motorway as a solid object that has caused this problem. The motorway actually is a fluid and dynamic thing, and it should be seen as such: in fact it’s not an organ at all but actually tissue – something that connects rather than is. Once we start to see the motorway as tissue, it opens up new propositions about what the motorway is, is used for and does. This new dynamic and connective view unlocks the stasis of the motorway as edifice, and allows adaptation to happen: adaptation to old contexts that were ignored by the planners, and adaptation to new contexts that have arisen because of or in spite of our best efforts.

Motorways as tissue are more than just infrastructures: they are landscapes. These landscapes can be seen as surfaces on which flows take place, not only of cars, buses and lorries, but also of the globalized goods carried and the lifestyles and mobilities enabled. Here the infinite speed of urban change of thought transcends the declared speed limit [70 mph] of the motorway, in that a consignment of bananas can cause soil erosion in Equador, or the delivery of a new iphone can unlock connections and ideas the world over.

So what is this new landscape to be like? It may be a parallax-shifting, cognitive looking glass; a drone scape of energy transformation; a collective farm, or maybe part of a hospital. But what’s for sure, is that it is never fixed nor static: it pulses like a heartbeat through that most bland of landscapes, the countryside. It transmits forces like a Caribbean hurricane creating surf on an Atlantic Storm Beach: alien forces that mutate and re-form these places screaming into new, unclear and unintended futures.

And this future is clear: the future is urban. In this small rural country, motorways as tissue have made the whole of it: countryside, mountain, sea and town, into one singular, homogenous and hyper-connected, generic city.

Goodbye, place. Hello, surface!