33 research outputs found
Palladium-Catalyzed Carbon-Carbon Bond-Forming Reactions with Unactivated Alkyl Electrophiles
I. Cross-Coupling Reactions with Alkyl Electrophiles An overview of the application of alkyl electrophiles in cross-coupling reactions is presented, highlighting the importance of this reactivity and challenges associated therein. Recent advances in alkyl cross-coupling are discussed, from both a process development and mechanistic perspective, to describe the current state of the field. Advances in hybrid organometallic-radical reactivity are also considered, with particular focus on its application in alkyl cross-coupling and perspective on mechanistic analysis. II. Palladium-Catalyzed Ring-Forming Aromatic C-H Alkylation A palladium-catalyzed, intramolecular aromatic C-H alkylation with unactivated alkyl halides is described. This process is successful with both iodides and bromides, including those with β-hydrogen atoms present. It also tolerates both electron-rich and electron-poor aromatic rings, as well as heteroaromatic substrates. The mild, palladium-catalyzed approach displays compatibility with a diverse range of functional groups, including those which are base- or nucleophile-sensitive. A mechanistic investigation is also presented, suggesting the presence of radical intermediates. III. A Versatile, Palladium-Catalyzed Approach to Alkene-Alkyl Halide Coupling A method for the palladium-catalyzed coupling of alkyl halides with alkenes is presented. Reaction conditions determine whether the end product retains the alkyl halide moiety in an atom-transfer radical cyclization (ATRC) reaction, or if the alkene component is restored, affecting a formal Heck-type transformation. The manifold is capable of performing both transformations with unactivated alkyl bromides and a variety of terminal, di- and tri-substituted alkenes under argon atmosphere. It also enables formation of both 5- and 6-membered rings. A mechanistic investigation of this reaction is presented, which suggests the operation of a catalytic, hybrid organometallic-radical process.Doctor of Philosoph
Integration and continuity of primary care: polyclinics and alternatives - a patient-centred analysis of how organisation constrains care co-ordination
Background
An ageing population, the increasing specialisation of clinical services and diverse health-care provider ownership make the co-ordination and continuity of complex care increasingly problematic. The way in which the provision of complex health care is co-ordinated produces – or fails to produce – six forms of continuity of care (cross-sectional, longitudinal, flexible, access, informational and relational). Care co-ordination is accomplished by a combination of activities by patients themselves; provider organisations; care networks co-ordinating the separate provider organisations; and overall health-system governance. This research examines how far organisational integration might promote care co-ordination at the clinical level.
Objectives
To examine (1) what differences the organisational integration of primary care makes, compared with network governance, to horizontal and vertical co-ordination of care; (2) what difference provider ownership (corporate, partnership, public) makes; (3) how much scope either structure allows for managerial discretion and ‘performance’; (4) differences between networked and hierarchical governance regarding the continuity and integration of primary care; and (5) the implications of the above for managerial practice in primary care.
Methods
Multiple-methods design combining (1) the assembly of an analytic framework by non-systematic review; (2) a framework analysis of patients’ experiences of the continuities of care; (3) a systematic comparison of organisational case studies made in the same study sites; (4) a cross-country comparison of care co-ordination mechanisms found in our NHS study sites with those in publicly owned and managed Swedish polyclinics; and (5) the analysis and synthesis of data using an ‘inside-out’ analytic strategy. Study sites included professional partnership, corporate and publicly owned and managed primary care providers, and different configurations of organisational integration or separation of community health services, mental health services, social services and acute inpatient care.
Results
Starting from data about patients’ experiences of the co-ordination or under-co-ordination of care, we identified five care co-ordination mechanisms present in both the integrated organisations and the care networks; four main obstacles to care co-ordination within the integrated organisations, of which two were also present in the care networks; seven main obstacles to care co-ordination that were specific to the care networks; and nine care co-ordination mechanisms present in the integrated organisations. Taking everything into consideration, integrated organisations appeared more favourable to producing continuities of care than did care networks. Network structures demonstrated more flexibility in adding services for small care groups temporarily, but the expansion of integrated organisations had advantages when adding new services on a longer term and a larger scale. Ownership differences affected the range of services to which patients had direct access; primary care doctors’ managerial responsibilities (relevant to care co-ordination because of their impact on general practitioner workload); and the scope for doctors to develop special interests. We found little difference between integrated organisations and care networks in terms of managerial discretion and performance.
Conclusions
On balance, an integrated organisation seems more likely to favour the development of care co-ordination and, therefore, continuities of care than a system of care networks. At least four different variants of ownership and management of organisationally integrated primary care providers are practicable in NHS-like settings. Future research is therefore required, above all to evaluate comparatively the different techniques for coordinating patient discharge across the triple interface between hospitals, general practices and community health services; and to discover what effects increasing the scale and scope of general practice activities will have on continuity of care
Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function
Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes
The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity
The microenvironment encompasses all components of a tumor other than the cancer cells themselves. It is highly heterogenous, comprising a cellular component that includes immune cells, fibroblasts, adipocytes, and endothelial cells, and a non-cellular component, which is a meshwork of polymeric proteins and accessory molecules, termed the extracellular matrix (ECM). The ECM provides both a biochemical and biomechanical context within which cancer cells exist. Cancer progression is dependent on the ability of cancer cells to traverse the ECM barrier, access the circulation and establish distal metastases. Communication between cancer cells and the microenvironment is therefore an important aspect of tumor progression. Significant progress has been made in identifying the molecular mechanisms that enable cancer cells to subvert the immune component of the microenvironment to facilitate tumor growth and spread. While much less is known about how the tumor cells adapt to changes in the ECM nor indeed how they influence ECM structure and composition, the importance of the ECM to cancer progression is now well established. Plasticity refers to the ability of cancer cells to modify their physiological characteristics, permitting them to survive hostile microenvironments and resist therapy. Examples include the acquisition of stemness characteristics and the epithelial-mesenchymal and mesenchymal-epithelial transitions. There is emerging evidence that the biochemical and biomechanical properties of the ECM influence cancer cell plasticity and vice versa. Outstanding challenges for the field remain the identification of the cellular mechanisms by which cancer cells establish tumor-promoting ECM characteristics and delineating the key molecular mechanisms underlying ECM-induced cancer cell plasticity. Here we summarize the current state of understanding about the relationships between cancer cells and the main stromal cell types of the microenvironment that determine ECM characteristics, and the key molecular pathways that govern this three-way interaction to regulate cancer cell plasticity. We postulate that a comprehensive understanding of this dynamic system will be required to fully exploit opportunities for targeting the ECM regulators of cancer cell plasticity.Valentina Poltavets, Marina Kochetkova, Stuart M. Pitson and Michael S. Samue
Palladium-Catalyzed, Ring-Forming Aromatic C–H Alkylations with Unactivated Alkyl Halides
A catalytic
C–H alkylation using unactivated alkyl halides
and a variety of arenes and heteroarenes is described. This ring-forming
process is successful with a variety of unactivated primary and secondary
alkyl halides, including those with β-hydrogens. In contrast
to standard polar or radical cyclizations of aromatic systems, electronic
activation of the substrate is not required. The mild, catalytic reaction
conditions are highly functional group tolerant and facilitate access
to a diverse range of synthetically and medicinally important carbocyclic
and heterocyclic systems
Palladium-Catalyzed Carbocyclizations of Unactivated Alkyl Bromides with Alkenes Involving Auto-tandem Catalysis
The development of a general catalytic
system for the palladium-catalyzed
carbocyclization of unactivated alkyl bromides with alkenes is described.
This approach uses a commercially available bisphosphine ligand and
avoids the use of carbon monoxide atmosphere present in prior studies
involving alkyl iodides. Detailed mechanistic studies of the transformation
are performed, which are consistent with auto-tandem catalysis involving
atom-transfer radical cyclization followed by catalytic dehydrohalogenation.
These studies also suggest that reactions involving alkyl iodides
may proceed through a metal-initiated, rather than metal-catalyzed,
radical chain process