Beyond Individualism: Social Work and Social Identity

Individualism continues to have a notable impact on social work. The personalisation of services and the individualisation of care are just two examples of this societal trend. While helping service users to articulate their aspirations for a better future, individualism, if taken too far, undermines the social aspects of life. In response to this concern, this paper argues that social work must appreciate the interplay between the individual and the collective spheres, and its impact on identity formation, in order to enhance human well-being. To give substance to this argument, Jenkins's model of social identity is appropriated and augmented to take account of four interlinked, yet distinct, orders of experience, namely the individual, interactional, institutional and societal orders. This reworked conceptualisation is then considered in terms of its implications for social work practice.

Utilising a computer game as a therapeutic intervention for youth in residential care: Some preliminary findings on use and acceptability

Mental illness is common amongst young people living in residential care, many of whom are reluctant to avail of therapeutic help. The potential value of computer games as therapeutic tools for these young people has received very little attention, despite indications of their potential for promoting engagement in therapeutic work and improving mental health outcomes. This study aimed to fill this research gap through the development, introduction, and preliminary evaluation of a therapeutic intervention in group care settings. The intervention incorporated a commercially available computer game (The SIMS Life Stories™) and emotion regulation skill coaching. Qualified residential social workers were trained to deliver it to young people in three children's homes in Northern Ireland, where therapeutic approaches to social work had been introduced. The research was framed as an exploratory case study which aimed to determine the acceptability and potential therapeutic value of this intervention. The evidence suggests that computer-game based interventions of this type may have value as therapeutic tools in group care settings and deserve further development and empirical investigation to determine their effectiveness in improving mental health outcomes.

Reducing Child Protection Error in Social Work: Towards an Holistic-Rational Perspective

Social work in the United Kingdom remains embroiled in concerns about child protection error. The serious injury or death of vulnerable children continues to evince much consternation in the public and private spheres. Governmental responses to these concerns invariably draw on technocratic solutions involving more procedures, case management systems, information technology and bureaucratic regulation. Such solutions flow from an implicit use of instrumental rationality based on a ‘means-end’ logic. While bringing an important perspective to the problem of child protection error, instrumental rationality has been overused limiting discretion and other modes of rational inquiry. This paper argues that the social work profession should apply an enlarged form of rationality comprising not only the instrumental-rational mode but also the critical-rational, affective-rational and communicative-rational forms. It is suggested that this combined, conceptual arsenal of rational inquiry leads to a gestalt which has been termed the holistic-rational perspective. It is also argued that embracing a more rounded perspective such as this might offer greater opportunities for reducing child protection error.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

Treatment of retinopathy of prematurity in Northern Ireland, 2000-2011: a population-based study

Purpose To evaluate the incidence of treatment-requiring retinopathy of prematurity (ROP) over a 12-year-period in Northern Ireland. Methods The medical records of all infants treated for ROP from January 2000 to December 2011were retrospectively reviewed and cross-referenced with the Neonatal Intensive Care Outcomes Research and Evaluation (NICORE) database. Results The Northern Ireland population data showed an increase in the number of live births from 2000 to 2011. The proportion of babies born with a birth weight <1501 g and/or <32 weeks’ gestational age remained constant (χ2 trend = 3.220, P = 0.0727), although the proportion of these babies who died prior to 42 weeks’ gestation decreased from 2000 to 2011 (P = 0.0196 using χ2 for trend = 5.445; P = 0.0354 using χ2 = 20.809). The prevalence of treatment-requiring ROP in these infants increased from 1.05% in 2000 to 5.78% in 2011 (P < 0.001 using χ2 trend = 16.309; P < 0.001 using χ2 = 31.378). Conclusions The present population-based study highlights that the incidence of treatment- requiring ROP is increasing in Northern Ireland. The increasing number of infants requiring treatment will need to be taken into consideration in the commissioning process for ROP services in Northern Ireland.

The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models

Colorectal cancer is the second most common cause of cancer-related death in the United States. Recent studies showed that interleukin-8 (IL-8) and its receptors (CXCR1 and CXCR2) are significantly upregulated in both the tumor and its microenvironment, and act as key regulators of proliferation, angiogenesis, and metastasis. Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. SCH-527123 showed concentration-dependent antiproliferative effects in HCT116, Caco2, and their respective IL-8-overexpressing variants colorectal cancer cell lines. Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-κB/mitogen-activated protein kinase (MAPK)/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in colorectal cancer cell lines. In vivo results verified that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors. Importantly, these preclinical studies showed that the combination of SCH-527123 and oxaliplatin resulted in a greater decrease in cell proliferation, tumor growth, apoptosis, and angiogenesis that was superior to single-agent treatment. Taken together, these findings suggest that targeting CXCR2 may block tumor proliferation, migration, invasion, and angiogenesis. In addition, CXCR2 blockade may further sensitize colorectal cancer to oxaliplatin treatment.

A novel fluorescence-based assay for the rapid detection and quantification of cellular deoxyribonucleoside triphosphates

Current methods for measuring deoxyribonucleoside triphosphates (dNTPs) employ reagent and labor-intensive assays utilizing radioisotopes in DNA polymerase-based assays and/or chromatography-based approaches. We have developed a rapid and sensitive 96-well fluorescence-based assay to quantify cellular dNTPs utilizing a standard real-time PCR thermocycler. This assay relies on the principle that incorporation of a limiting dNTP is required for primer-extension and Taq polymerase-mediated 5-3' exonuclease hydrolysis of a dual-quenched fluorophore-labeled probe resulting in fluorescence. The concentration of limiting dNTP is directly proportional to the fluorescence generated. The assay demonstrated excellent linearity (R(2) > 0.99) and can be modified to detect between ∼0.5 and 100 pmol of dNTP. The limits of detection (LOD) and quantification (LOQ) for all dNTPs were defined as <0.77 and <1.3 pmol, respectively. The intra-assay and inter-assay variation coefficients were determined to be <4.6% and <10%, respectively with an accuracy of 100 ± 15% for all dNTPs. The assay quantified intracellular dNTPs with similar results obtained from a validated LC-MS/MS approach and successfully measured quantitative differences in dNTP pools in human cancer cells treated with inhibitors of thymidylate metabolism. This assay has important application in research that investigates the influence of pathological conditions or pharmacological agents on dNTP biosynthesis and regulation.

The dual EGFR/HER2 inhibitor lapatinib synergistically enhances the antitumor activity of the histone deacetylase inhibitor panobinostat in colorectal cancer models

As key molecules that drive progression and chemoresistance in gastrointestinal cancers, epidermal growth factor receptor (EGFR) and HER2 have become efficacious drug targets in this setting. Lapatinib is an EGFR/HER2 kinase inhibitor suppressing signaling through the RAS/RAF/MEK (MAP/ERK kinase)/MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase)/AKT pathways. Histone deacetylase inhibitors (HDACi) are a novel class of agents that induce cell cycle arrest and apoptosis following the acetylation of histone and nonhistone proteins modulating gene expression and disrupting HSP90 function inducing the degradation of EGFR-pathway client proteins. This study sought to evaluate the therapeutic potential of combining lapatinib with the HDACi panobinostat in colorectal cancer (CRC) cell lines with varying EGFR/HER2 expression and KRAS/BRAF/PIK3CA mutations. Lapatinib and panobinostat exerted concentration-dependent antiproliferative effects in vitro (panobinostat range 7.2-30 nmol/L; lapatinib range 7.6-25.8 μmol/L). Combined lapatinib and panobinostat treatment interacted synergistically to inhibit the proliferation and colony formation in all CRC cell lines tested. Combination treatment resulted in rapid induction of apoptosis that coincided with increased DNA double-strand breaks, caspase-8 activation, and PARP cleavage. This was paralleled by decreased signaling through both the PI3K and MAPK pathways and increased downregulation of transcriptional targets including NF-κB1, IRAK1, and CCND1. Panobinostat treatment induced downregulation of EGFR, HER2, and HER3 mRNA and protein through transcriptional and posttranslational mechanisms. In the LoVo KRAS mutant CRC xenograft model, the combination showed greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer preclinical rationale warranting further clinical investigation combining HDACi with EGFR and HER2-targeted therapies for CRC treatment.

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38

Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). Lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas.

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!