Building a relational capability in business service relationships: the exploration of learning needs in stages of relationship development

Context and Objectives: There is an increasing recognition that there is great potential in utilizing learning in client relationships as this can enable service providers to develop relational capabilities and more successfully manage relationships. Building on this premise, the present study argues that learning in relationships relates to the ability to learn from the local context to leverage relationship success. To do this, requires an understanding of what drives success in each stage of relationship development and how this can be achieved to ensure success. The aim of the research is to explore the potential for learning in business service relationships, through the exploration of learning needs relevant in stages of relationship development. Learning needs are defined as what service providers need to learn about how to leverage successful relationships at each stage of development. Research Methodology: The study employs two qualitative case studies of business service providers that provide contextually differing embedding conditions for relationships and learning. Data has been gathered through interviews with individual service providers, observation of practice and organisational documentation. The research undertaken explores service providers’ approach towards relationship development, with the aim of identifying critical factors influencing success in each relationship stage and corresponding opportunities for learning through the experiences and challenges faced by service providers in practice. Findings: Results highlights that learning from the local context is critical for managing relationship success. Critical success factors for each stage are identified from the experiences and challenges faced by service providers across the two cases. These are translated into learning needs for each stage that aim to guide service providers’ attempts to learn from the local context in order to inform and adapt their approach. The appreciation of learning needs in relation to the unique context of each organisation directs attention to corresponding guidelines for practice. The research concludes with the proposition of a theoretical model for learning in relationships as well as a practical learning needs framework that can be incorporated in service providers’ practices for managing client relationships. Importantly results suggest that becoming relationally capable requires a transition to embracing a learning orientation in terms of both philosophy and process. Research Relevance and Implications: The study extends the potential for the creation of a relational capability in business relationships through the exploration of learning needs. Findings suggest that relationship management can be viewed as a cyclical process of learning and adaptation where success at each stage rests on the ability to read and learn from the local context and engage in appropriate actions in practice. The study contributes towards practice, by providing a practical framework through which service providers can develop relational learning. Exploration and appreciation of learning needs in stages of relationship development can aid service providers in the establishment of appropriate approaches towards intervention or stimulation of relationship success

Le complexe GIT-PIX : Une plate-forme de régulation des GTPases ARF et Rac/Cdc42

Les protéines G sont des commutateurs moléculaires contrôlant divers aspects de la vie cellulaire tels que la transduction du signal, la réorganisation du cytosquelette et les mécanismes de transport vésiculaire. Ces protéines fixent alternativement les nucléotides GDP et GTP, ce qui leur permet de transiter entre deux conformations structurelles, respectivement inactive et active. L’activation des protéines G résulte d’une interaction avec un facteur d’échange qui stimule la dissociation du GDP pour le remplacer par du GTP. C’est sous cette forme liée au GTP que les protéines G vont pouvoir interagir avec leurs effecteurs et les activer. La stimulation de l’activité intrinsèque d’hydrolyse des protéines G par des protéines GAP (GTPase activating protein) va conduire à un retour vers la forme inactive liée au GDP. De nombreuses études ont montré l’existence d’interconnexions entre les voies de signalisation impliquant les GTPases ARF (ADP ribosylation factor) et Rac/Cdc42. La découverte d’un complexe protéique comprenant PIX, un facteur d’échange pour Rac/Cdc42 et GIT1, une protéine GAP pour les ARF, a récemment donné un nouvel éclairage sur les moyens mis en oeuvre par la cellule pour réguler de façon étroite l’agencement du cytosquelette et la dynamique des membranes. De plus, la plate-forme PIX-GIT1 est associée à des réseaux de signalisation comprenant des suppresseurs de tumeur. Ces données récentes incitent à prendre ce complexe en considération dans le contexte des pathologies cancéreuses.We recently described that the tumor suppressor factor Scribble anchors the PIX exchange factor for Rac/Cdc42 and the ARF-GAP GIT proteins at the plasma membrane. Because it has been postulated that the GIT-PIX proteins dimerize and tightly self-assemble to form a high molecular weight complex, this nexus may be capable of linking together important signalling molecules to control cytosqueleton polymerization and membrane dynamics. To date, most studies that have tempted to unravel the function of these proteins have found their implication in a great variety of cellular functions (receptor recycling, endo-exocytosis, cell migration, synapse formation…) but have mostly neglected to consider the multimeric organization of this hub. There is no doubt that our comprehension of physiopathological disorders such as cancers will be improved when the nature of the complex pathways integrated by the GIT-PIX nodule will be understood

Superior outcomes of nodal metastases compared to visceral sites in oligometastatic colorectal cancer treated with stereotactic ablative radiotherapy

Background: Stereotactic ablative radiotherapy (SBRT) is a radical option for oligometastatic colorectal cancer (CRC) patients, but most data relate to visceral metastases. Methods: A prospective, multi-centre database of CRC patients treated with SBRT was interrogated. Inclusion criteria were ECOG PS 0–2, ≤3 sites of disease, a disease free interval of >6 months unless synchronous liver metastases. Primary endpoints were local control (LC), progression free survival (PFS) and overall survival (OS). Results: 163 patients (172 metastases) were analysed. The median FU was 16 months (IQR 12.2–22.85). The LC at 1 year was 83.8% (CI 76.4%−91.9%) with a PFS of 55% (CI 47%−64.7%) respectively. LC at 1 year was 90% (CI 83%−99%) for nodal metastases (NM), 75% (63%−90%) for visceral metastases (VM). NM had improved median PFS (9 vs 19 months) [HR 0.6, CI 0.38–0.94, p = 0.032] and median OS (32 months vs not reached) [HR 0.28, CI 0.18–0.7, p = 0.0062] than VM, regardless of whether the NM were located inside or outside the pelvis. On multivariate analysis, NM and ECOG PS 0 were significant good prognostic factors. An exploratory analysis suggests KRAS WT is also a good prognostic factor. Conclusion: Nodal site is an important prognostic determinant of SBRT that should incorporated into patient selection. We hypothesise this may have an immunoediting basis

Residential exposure to motor vehicle emissions and the risk of wheezing among 7-8 year-old schoolchildren: a city-wide cross-sectional study in Nicosia, Cyprus

<p>Abstract</p> <p>Background</p> <p>Several studies have reported associations between respiratory outcomes in children and a range of self-reported, administrative or geographical indicators of traffic pollution. First-time investigation into the frequency of asthmatic symptoms among 7-8 year-old Cypriot children in 1999-2000 showed increased prevalence in the capital Nicosia compared to other areas. Geographical differences on an island the size of Cyprus may reflect environmental and/or lifestyle factors. This study investigates the relationship between self-reported symptoms and residential exposure to motor vehicle emissions among Nicosia schoolchildren.</p> <p>Methods</p> <p>The addresses of children in the metropolitan area of Nicosia who participated in the original survey (N = 1,735) were geo-coded and the level of exposure of each child was assessed using distance- and emission-based indicators (i.e. estimated levels of particulate matter and nitrogen oxides emissions due to motor vehicles on main roads around the residence). Odds ratios of wheezing and asthma diagnosis in relation to levels of exposure were estimated in logistic regression models adjusting for person-based factors, co-morbidity and intra-school clustering.</p> <p>Results</p> <p>We found an increased risk of wheezing at distances less than 50 m from a main road and/or only among those experiencing the highest levels of exposure. The strongest effect estimates were observed when exposure was defined in terms of the cumulative burden at all roads around the residence. Adjusted odds ratios for current wheezing were 2.33 (95% CI 1.27, 4.30) amongst the quartile of participants exposed to the highest levels of PM at all roads 50 m of their residence and 2.14 (95% CI 1.05, 4.35) for NOx, with no effect at intermediate levels of exposure. While the direction of effect was apparent at longer distances, differences were generally not statistically significant.</p> <p>Conclusions</p> <p>Children experiencing the highest burden of emissions in Nicosia seem to be at a higher risk of reporting asthmatic symptoms. Due to the small number of children residing at close proximity to main roads and lack of evidence of risk at intermediate levels of exposure or longer distances, the observed pattern alone does not explain the generally higher prevalence observed in urban Nicosia compared to other areas.</p

A syndromic form of X-linked mental retardation: the Coffin-Lowry syndrome

Coffin-Lowry syndrome (CLS, OMIM 303600) is an X-linked inherited disorder characterised in male patients by growth and psychomotor retardation, hypotonia and progressive skeletal changes. Typically, male patients are of short stature and exhibit a characteristic coarse face with a prominent forehead, orbital hypertelorism, downslanting palpebral fissures, thick lips, a thick nasal septum with anteverted nares, and irregular or missing teeth. Their large and soft hands with lax skin and tapering fingers, are usually a strong diagnostic feature. Some patients present with additional complications including, sensorineural deafness, seizures, drop episodes and cardiac disease. There is some variability in the mental development of affected males, but most of the males who receive appropriate care appear to be moderately affected. A majority of carrier females have only minimal findings (mild facial coarsening, tapering fingers and obesity). Early diagnosis of CLS is essential for proper management, including survey of some specific complications already mentioned, and for genetic counselling. Establishing the diagnosis in very young children is often much more difficult than in older patients since physical characteristics are milder and not specific. Loss of function mutations in the gene encoding the growth-factor induced protein kinase ribosomal S6 kinase are responsible for CLS. A mutation has been detected in about 50% of patients with clinical features suggestive of CLS, and over 80 different mutations have so far been identified. They are distributed throughout the gene, the vast majority being unique to single families and a high proportion appear to be de novo events. Some missense mutations are associated with milder phenotypes. In one family, a missense mutation was associated solely with mild mental retardation and no other clinical feature. CONCLUSION: Coffin-Lowry syndrome is a well characterised entity and a detailed clinical examination usually allows diagnosis. However, recognising it in very young children is often difficult since physical characteristics are mild and not specific. In addition, most cases are sporadic. Screening for ribosomal S6 kinase mutations is essential in most cases to confirm the diagnosis as well as for genetic counselling

Behandlingsplanering med nya frihetsgrader för Strålkniven

The Leksell Gamma Knife® is an instrument designed for high precision treatment of tumours and lesions located in the brain and upper spine. Today, the radioactive cobalt-60 sources can only move linearly along the radiation unit, but the machine could be modified to include rotational motion as well. We extend an existing linear programming approach to inverse planning for the Gamma Knife by examining the benefits from rotational degrees of freedom. The improvements offered from rotations are limited, but easy to make use of. We investigate the model in four patient cases, and find that an upper bound on the improvement of the optimization cost function is between 4.5% and 7.0% depending on case. With a total of four angles distributed uniformly over a 45 degree interval, one can in each case achieve a solution that performs up to within 1% of this bound. The average maximal improvements in terms of clinical metrics are 0.5% selectivity and 1.9% gradient index, at the cost of 5.9% worse beam-on time. No statistically significant change in coverage is found. A dynamic model based on column generation is proposed, which allows treatment during constant velocity angular motion and can achieve practically the same plan quality as the model with uniformly distributed angles at a significantly lower problem size. A similar algorithm can be designed to locate the most effective angles in a non-uniform manner that achieves better plans with fewer added rotational degrees of freedom. Trade-offs between memory and solution times are used to successively reduce the RAM occupation by around 90% and make significantly larger models computationally feasible to solve. A voxel clustering approach with emphasis on surface voxels, adapted to the radiosurgical framework, can significantly reduce the problem size while still producing competitive plans.Strålkniven Leksell Gamma Knife® är ett instrument designat för högprecisionsbestrålning av tumörer och lesioner i hjärnan och övre delen av ryggraden. Idag kan de radioaktiva källorna endast förflyttas linjärt under behandlingen, men maskinen skulle kunna modifieras för att även tillåta rotationsrörelser. Vi utvidgar ett ramverk för inversplanering, formulerat som ett linjär-programmeringsproblem, genom att undersöka fördelarna med nya rotationsfrihetsgrader. Förbättringarna som rotationer möjliggör är begränsade, men kan relativt enkelt tas till vara. Vi undersöker de potentiella förändringarna i fyra patientfall och finner att den övre gränsen av förbättringarna för målfunktionsvärdet i optimeringsproblemet är mellan 4.5% och 7.0% beroende på fall. Genom att tillåta rotation av källorna till fyra jämnt fördelade vinklar över 45 grader kan man i samtliga fall hitta en lösning som är inom 1% från det bästa målfunktionsvärdet. De genomsnittliga förbättringarna i form av kliniska metriker är 0.5% selektivitet och 1.9% gradient-index, dock på bekostnad av en försämring av bestrålningstiden med 5.9%. Ingen tydlig förändring av täckningen kunde påvisas. En modell baserad på kolumngenerering, som tillåter behandling under rotation av kollimator-kroppen med konstant hastighet, föreslås. I denna modell kan praktiskt taget lika bra lösningar uppnås som för likformigt fördelade vinklar, men med betydligt mindre problemstorlek. En liknande algoritm kan lokalisera de mest effektiva vinklarna och åstadkomma samma plankvalitet med färre, men olikformt fördelade, rotationsfrihetsgrader. RAM-användningen kan reduceras med cirka 90% genom avvägningar mellan minne och beräknings-tider, vilket möjliggör lösning av probleminstanser som tidigare var beräkningsmässigt omöjliga. Klustringsmetoder av voxlar anpassade till strålkniven kan minska problemstorleken betydelsefullt medan de resulterande behandlingsplanerna är fortsatt konkurrenskraftiga

Delineation of the mechanisms of aberrant splicing caused by two unusual intronic mutations in the RSK2 gene involved in Coffin–Lowry syndrome

Coffin–Lowry syndrome (CLS) is caused by mutations in the RSK2 gene encoding a protein kinase of the Ras signalling pathway. We have studied two point mutations which cause aberrant splicing but do not concern the invariant GT or AG nucleotides of splice sites. The first, an A→G transition at position +3 of the 5′ splice site of exon 6, results in vivo and in vitro in exon skipping and premature translation termination. The natural 5′ splice site, although intrinsically weak, is not transactivated under normal conditions. Consequently, replacement of an A/U by a G/U base pairing with U1 snRNA reduces its strength below a critical threshold. The second mutation, an A→G transition 11 nt upstream of exon 5, creates a new AG near the natural 3′ splice site. In vitro this synthetic 3′ AG is used exclusively by the splicing machinery. In vivo this splicing event is also observed, but is underestimated because the resulting RSK2 mRNA contains premature stop codons which trigger the nonsense-mediated decay process. We show that a particular mechanism is involved in the aberrant splicing of exon 5, implying involvement of the natural 3′ AG during the first catalytic step and the new 3′ AG during the second step. Thus, our results explain how these mutations cause severe forms of CLS

Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin-Lowry syndrome

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation that is characterized, in male patients, by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological hand aspects exhibited by patients are essential clues for the diagnosis. CLS is caused by mutations in a gene that is located in Xp22.2 and that encodes RSK2, a growth-factor-regulated protein kinase. RSK2 mutations are extremely heterogeneous and lead to premature termination of translation and/or loss of phosphotransferase activity. Surprisingly, among a series of 250 patients screened by single-strand conformation polymorphism (SSCP) analysis, in whom a clinical diagnosis of CLS was made, no mutations were detected in 66% (165) of the patients. To determine what proportion of these latter patients have a RSK2 mutation that has not been detected and what proportion have different disorders that are phenotypically similar to CLS, we have, in the present article, investigated, by western blot analysis and in vitro kinase assay, cell lines from 26 patients in whom no mutation was previously identified by SSCP analysis. This approach allowed us to identify seven novel RSK2 mutations: two changes in the coding sequence of RSK2, one intragenic deletion, and four unusual intronic nucleotide substitutions that do not affect the consensus GT or AG splice sites. We have also determined the nucleotide sequence of the promoter region of the RSK2 gene, and we have screened it for mutations. No disease-causing nucleotide change was identified, suggesting that mutations affecting the promoter region are unlikely to account for a large number of patients with CLS. Finally, our results provide evidence that some patients have a disease that is phenotypically very similar to CLS, which is not caused by RSK2 defects. This suggests that there are defects in either additional genes or combinations of genes that may result in a CLS-like phenotype

Cancer Stem Cell Quiescence and Plasticity as Major Challenges in Cancer Therapy

Cells with stem-like properties, tumorigenic potential, and treatment-resistant phenotypes have been identified in many human malignancies. Based on the properties they share with nonneoplastic stem cells or their ability to initiate and propagate tumors in vivo, such cells were designated as cancer stem (stem-like) or tumor initiating/propagating cells. Owing to their implication in treatment resistance, cancer stem cells (CSCs) have been the subject of intense investigation in past years. Comprehension of CSCs’ intrinsic properties and mechanisms they develop to survive and even enhance their aggressive phenotype within the hostile conditions of the tumor microenvironment has reoriented therapeutic strategies to fight cancer. This report provides selected examples of malignancies in which the presence of CSCs has been evidenced and briefly discusses methods to identify, isolate, and functionally characterize the CSC subpopulation of cancer cells. Relevant biological targets in CSCs, their link to treatment resistance, proposed targeting strategies, and limitations of these approaches are presented. Two major aspects of CSC physiopathology, namely, relative in vivo quiescence and plasticity in response to microenvironmental cues or treatment, are highlighted. Implications of these findings in the context of the development of new therapies are discussed