Stability data, irregular connections and tropical curves

We study a class of meromorphic connections nabla(Z) on P^1, parametrised by the central charge Z of a stability condition, with values in a Lie algebra of formal vector fields on a torus. Their definition is motivated by the work of Gaiotto, Moore and Neitzke on wall-crossing and three-dimensional field theories. Our main results concern two limits of the families nabla(Z) as we rescale the central charge Z to RZ. In the R to 0 ``conformal limit'' we recover a version of the connections introduced by Bridgeland and Toledano Laredo (and so the Joyce holomorphic generating functions for enumerative invariants), although with a different construction yielding new explicit formulae. In the R to infty ``large complex structure" limit the connections nabla(Z) make contact with the Gross-Pandharipande-Siebert approach to wall-crossing based on tropical geometry. Their flat sections display tropical behaviour, and also encode certain tropical/relative Gromov-Witten invariants

Exploring the scope and utility of dynamic covalent chemistry within polymeric nanoparticles

Dynamic covalent chemistry encompasses reversible bond forming reactions which proceed under equilibrium control, where the position of the equilibria are sensitive to changes in environment, and which are often able to undergo component exchange. These virtues provide polymeric nanoparticles incorporating dynamic covalent bonds with the ability to reconfigure or change their structural properties in response to stimuli. In Chapter 1 we critically discuss and evaluate the current state of the art whereby polymer chemists have exploited dynamic covalent bonds within responsive and adaptive polymeric nanoparticles. Chapter 2 describes the synthesis and study of a chemoresponsive polymeric micelle. In this work, aldehyde and alkoxyamine endfunctionalized polymers are shown to link together through a single oxime bond and then self-assemble into micellar aggregates. The chemoresponsive nature of these micellar aggregates is expressed when their disassembly is triggered through the addition of a small molecule alkoxyamine. Chemoresponsive core cross-linked star and nanogel nanoparticles which contain multiple imine cross-links are presented in Chapter 3. These imine linkages are utilized to facilitate the self-assembly process of the nanoparticles, which display chemoresponsive disassembly upon the addition of a small molecule amine. Chapter 4 describes the preparation of core cross-linked star polymers which are both pH-responsive and thermoresponsive. The pH-responsive nature is imparted through the pH-responsiveness of multiple imine linkages, and their thermoresponsive nature arises on account of the thermoresponsive polymer chains contained within their cores. In Chapter 5 nanoparticles possessing pH-responsive imine and redox-responsive disulfide cross-links have been developed where the simultaneous application of both low pH and a reducing agent is required to trigger their disassembly. It is shown that the application of either low pH or a reducing agent does not trigger disassembly. The research presented throughout this dissertation confirms the great potential of dynamic covalent chemistry in the development of stimuliresponsive polymeric nanoparticles.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Gastric aspiration, epithelial injury and chronic lung allograft rejection

Introduction For patients with a variety of end stage lung diseases, lung transplantation has become an effective therapy. Chronic allograft rejection occurs in over 50% of patients 5 years post transplantation however. Although alloimmune-mediated injury directed against endothelial and epithelial structures were traditionally thought to be the major culprit, non-alloimmunologic inflammation after bile acid aspiration has been implicated in cystic fibrosis (CF) lung injury, after transplantation. Hypothesis Reflux with aspiration of bile acid is present in the lower airways of people with cystic fibrosis associated lung injury before and after transplantation. Bile acid challenge would cause cytoxicity and release of inflammatory mediators from patient derived primary epithelial cells (PBECs), before and after transplantation. Methods PBECs from lung transplantation patients, explanted CF patient cultures and a goblet cell line were used to perform proof of concept experiments. In these experiments the effect of individual primary and secondary bile acids, porcine pepsin, different patient derived gastric juices (whole or filtered and dialysed) samples and an artificial bile acid mixture were evaluated. Cell death, Interleukin 8 (IL-8), Interleukin 6 (IL-6) and Granulocyte Macrophage Colony Stumulating Factor (GMCSF) production were measured by Titer blue and multiplex ELISA. Results Epithelial cells can be cultured successfully from the bronchial brushings of lung transplant recipient, CF patient explanted lungs and a Goblet cell line. In work connected with this study my research group has demonstrated that the lungs of people with advanced CF lung disease removed at the time of transplantation contained significant levels of bile acids higher than expected based on normal serum levels. I therefore tested the effects of bile acids on PBECs from lung transplant and CF patients. Challengesof ≥10mol/l was associated with significant cell death. Potentially physiological challenges with 1, 5 and 10 mol/l bile acids led to a significant release of pro-neutrophilic cytokines from lung transplant PBECs and CF PBECs .The goblet cell line HT-29 MTX was resistant to bile acids. Conclusion Aspiration of bile acids in CF lungs before and after transplantation may cause cell damage and inflammation. This injury may benefit from medical and surgical treatments for reflux, which may benefit the lung allograft generally.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Ethical, social and economic issues in familial breast cancer: a compilation of views from the EC biomed II demonstration project

ABSTRACT: Demand for clinical services for familial breast cancer is continuing to rise across Europe. Service provision is far from uniform and, in most centres, its evolution has been determined by local conditions, specifically by local research interests, rather than by central planning. However, in a number of countries there is evidence of progress towards co-ordinated development and audit of clinics providing risk assessment, counselling, screening and, in some cases, prophylactic intervention. Much important information should emerge from continued observation and comparative assessment of these developments. In most countries for which relevant data are available, there is a distinct bias towards higher social class among those who avail themselves of clinic facilities (in line with findings from many other health-promotion initiatives). This should be addressed when considering future organisation of clinical services. Molecular genetic studies designed to identify the underlying mutations responsible for familial breast cancer are not generally regarded as part of the clinical service and are funded through research grants (if at all). Economic considerations suggest that there is a case for keeping this policy under review. Familial cancers throw into sharp relief certain ethical and legal issues that have received much recent attention from government advisory bodies, patients ’ representatives, professional commentators and the popular media. Two are of particular importance; first, the right to gain access to medical records of relatives, in order to provide accurate risk assessment for a given family member, versus the right to privacy in respect of personal medical information and, second, the obligation (or otherwise) to inform family members of their risk status if they have not actively sought that knowledge. The legal position seems to vary from country to country and, in many cases, is unclear. In view of pressures to establish uniform approaches to medical confidentiality across the EC, it is important to evaluate the experience of participants in this Demonstration Programme and to apply the principle of “ non-malfeasance ” in formulating regu- lations that should govern future practice in this field. Data on economic aspects of familial breast cancer are remarkably sparse and outdated. As evidence accrues on the influence of screening and intervention programmes on morbidity and mortality, there is a strong case for evaluating the cost-effectiveness of different models of service provisi

Risk estimation as a decision-making tool for genetic analysis of the breast cancer susceptibility genes. EC Demonstration Project on Familial Breast Cancer.

For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing. We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures. Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing. Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families. The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20]. Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2. For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test. Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families

Utilisation of prophylactic mastectomy in 10 European centers

ABSTRACT: Increasingly women at high risk of breast cancer are opting for prophylactic surgery to reduce their risks. Data from 10 European centres that offer a risk counselling and screening service to women at risk show different approaches to the option of preventive surgery, although most centres adhere to a protocol including at least two risk counselling sessions and a psychological assessment. Thus far the combined centres have data on 174 women who have undergone prophylactic mastectomy with in excess of 400 women years of follow up. Operations were carried out on women with lifetime risks of 25–80%, with an average annual expected incidence rate of 1% per women. No breast cancers have occurred in this cohort. Long term follow up on an extended group of women will be necessary to truly address the risk of subsequent breast cancer and the psychological sequelae

Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes

In familial cutaneous malignant melanoma (CMM), disruption of the retinoblastoma (pRB) pathway frequently occurs through inactivating mutations in the p16 (p16INK4A/CDKN2A/MTS1) gene or activating mutations in the G1-specific cyclin dependent kinase 4 gene (CDK4). Uveal malignant melanoma (UMM) also occurs in a familial setting, or sometimes in association with familial or sporadic CMM. Molecular studies of sporadic UMM have revealed somatic deletions covering the INK4A-ARF locus (encoding P16INK4Aand P14ARF) in a large proportion of tumours. We hypothesized that germline mutations in the p16INK4A, p14ARFor CDK4 genes might contribute to some cases of familial UMM, or to some cases of UMM associated with another melanoma. Out of 155 patients treated at the Institut Curie for UMM between 1994 and 1997, and interviewed about their personal and familial history of melanoma, we identified seven patients with a relative affected with UMM (n = 6) or CMM (n = 1), and two patients who have had, in addition to UMM, a personal history of second melanoma, UMM (n = 1), or CMM (n = 1). We screened by polymerase chain reaction single-strand conformation polymorphism the entire coding sequence of the INK4A-ARF locus (exon 1α from p16INK4A, exon 1β from p14ARF, and exons 2 and 3, common to both genes), as well as the exons 2, 5 and 8 of the CDK4 gene, coding for the functional domains involved in p16 and/or cyclin D1 binding. A previously reported polymorphism in exon 3 of the INK4A-ARF locus was found in one patient affected with bilateral UMM, but no germline mutations were detected, either in the p16INK4A, p14ARFor CDK4 genes. Our data support the involvement of other genes in predisposition to uveal melanoma. © 2000 Cancer Research Campaig

Synthesis and biological studies on dinuclear gold(I) complexes with Di-(N-Heterocyclic Carbene) ligands functionalized with carbohydrates

The design of novel metal complexes with N-heterocyclic carbene (NHC) ligands that display biological activity is an active research field in organometallic chemistry. One of the possible approaches consists of the use of NHC ligands functionalized with a carbohydrate moiety. Two novel Au(I)-Au(I) dinuclear complexes were synthesized; they present a neutral structure with one bridging diNHC ligand, having one or both heterocyclic rings decorated with a carbohydrate functionality. With the symmetric diNHC ligand, the dicationic dinuclear complex bearing two bridging diNHC ligands was also synthesized. The study was completed by analyzing the antiproliferative properties of these complexes, which were compared to the activity displayed by similar mononuclear Au(I) complexes and by the analogous bimetallic Au(I)-Au(I) complex not functionalized with carbohydrates