Development of in vitro and in vivo models to underpin advances in human radiotherapy

Radiotherapy (RT) is commonly used for the local control of many cancer types. Unfortunately, not all patients will achieve a therapeutic benefit, and some will develop loco-regional recurrences and/or metastatic disease. The hypoxic nature of the tumour microenvironment and the development of radioresistant cancer cells can contribute to these treatment failures. Understanding the mechanisms involved in acquired radioresistance and the development of techniques to identify and target hypoxic tumour areas has the potential to improve RT response rates. The first aim of this project was to investigate the development of acquired radioresistance and identify radiation-induced secreted biomarkers which could be used as indicators of a radiation response or radiosensitivity. Human radioresistant (RR) breast cancer cell lines were developed from parental MCF-7, ZR-751 and MDA-MB-231 cells. Parental and RR cells underwent genotypic, phenotypic and functional characterisation. RR cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal transition. MCF-7 RR and ZR-751 RR cell lines exhibited significant phenotypic changes, including loss of ERα and PgR expression and increased EGFR expression, which were associated with the down-regulation of ER signalling genes and up-regulation of genes associated with PI3K, MAPK and WNT pathway activation. A change in subtype classification from luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes was also observed, consistent with radiation and endocrine therapy resistance and a more aggressive phenotype. To identify biomarkers secreted in response to radiation, human and canine breast and ovine lung cancer cell lines were radiated. Secretome samples were analysed by liquid chromatography-mass spectrometry. Using results from the MCF- 7 cell line, 33 radiation-induced secreted biomarkers were identified which had higher (up to 12-fold) secretion levels compared to untreated controls. Based on secretion profiles and functional analysis 9 candidate biomarkers were selected (YBX3, TK1, SEC24C, EIF3G, EIF4EBP2, NAP1L4, VPS29, GNPNAT1 and DKK1) of which the first 4 underwent in-lab validation. To identify biomarkers related to radiosensitivity transcriptomic analysis identified higher expression of genes encoding 7 of the candidate biomarkers in the MCF-7 cell line compared to its radioresistant derivative. WB analysis identified increased levels of the 4 biomarkers in the conditioned media of parental cells 24 h post-radiation which was not seen in the RR cell lines. These biomarkers, which had differential gene expression and secretion profiles between parental and RR cell lines, may be useful for both predicting and monitoring a tumour’s response to RT. A further aim was to investigate the biocompatibility and functionality of an implantable electrochemical sensor, developed within the Engineering and Physical Sciences Research Council funded IMPACT project. This sensor was designed to measure tissue O2 tension (ptO2) within a tumour, enabling the identification and monitoring of radioresistant hypoxic tumour areas. This study developed a novel in vivo tumour xenograft model to evaluate the potential of 6 materials (silicon dioxide, silicon nitride, Parylene-C, Nafion, biocompatible EPOTEK epoxy resin and platinum) used in the construction of the sensor, to trigger a foreign body response (FBR) when implanted into a solid tumour. Following implantation none of the materials affected tumour growth and all mice remained healthy. Immunohistochemistry performed on the tumour showed no significant changes in necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration or collagen deposition around the implant site. The absence of a FBR supports their use in the construction of implantable medical devices. In vivo validation of the O2 sensor to provide real-time measurements on intra-tumoural ptO2 was performed using a novel large animal ovine model. To achieve this aim, we developed a novel computed tomography (CT) guided transthoracic percutaneous implantation technique for the delivery of sensors into naturally occurring ovine pulmonary adenocarcinoma (OPA) tumours. This model successfully integrated techniques such as ultrasound, general anaesthesia, CT and surgery into the OPA model, all of which are techniques commonly used in the treatment of human lung cancer patients. This methodology resulted in the accurate implantation of sensors into OPA tumours with minimal complications and demonstrated the sensor’s ability to detect changes in intra-tumoural ptO2 following manipulation of the inspired fractional O2 concentration (FiO2). To investigate other possible clinical applications, sensors were validated for measuring intestinal ptO2 using a novel rat model. These experiments assessed the potential of the sensor to monitor intestinal perfusion following an intestinal resection and anastomosis. The sensor was placed onto the serosal surface of the small intestine of anaesthetised rats that were subsequently exposed to ischaemic, hypoxaemic and haemorrhagic insults. Decreases in intestinal ptO2 were observed following superior mesenteric artery occlusion and reductions in FiO2; these changes were reversible after reinstating blood flow or increasing FiO2. These results provided evidence that the sensors could detect changes in intestinal perfusion which could be utilised in a clinical setting to monitor peri-anastomotic intestinal ptO2. Overall this PhD project has conducted both in vitro and in vivo work aimed at the investigation of mechanisms of radioresistance, identifying secreted biomarkers of radiosensitivity and validating the ability of an implantable sensor to measure real-time intra-tumoural and visceral surface O2 tension. Identification of factors contributing to poor RT responses, such as radioresistance development and hypoxic tumour areas could provide a means by which RT could become personalised. Patients identified as having radioresistant tumours or those not responding to RT based on radiation-induced secreted biomarkers, could be given higher dose of radiation or radiosensitising agents to improve patient outcomes

Transient Demyelination Increases the Efficiency of Retrograde AAV Transduction

Adeno-associated virus (AAV) is capable of mediating retrograde viral transduction of central and peripheral neurons. This occurs at a relatively low efficiency, which we previously found to be dependent upon capsid serotype. We sought to augment retrograde transduction by providing increased axonal access to peripherally delivered AAV. Others have described utilizing full transection of peripheral nerves to mediate retrograde viral transduction of motor neurons. Here, we examined the ability of a transient demyelinating event to modulate levels of retrograde AAV transduction. Transient demyelination does not cause lasting functional deficits. Ethidium bromide (EtBr)–induced transient demyelination of the sciatic nerve resulted in significant elevation of retrograde transduction of both motor and sensory neurons. Retrograde transduction levels of motor neurons and heavily myelinated, large-diameter sensory neurons increased at least sixfold following peripheral delivery of self-complementary AAV serotype 1 (scAAV1) and serotype 2 (scAAV2), when preceded by demyelination. These findings identify a means of significantly enhancing retrograde vector transport for use in experimental paradigms requiring either retrograde neuronal identification and gene expression, or translational treatment paradigms

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good