T cell delivery of immune-stimulatory cytokines to enhance cancer immunotherapy

Adoptive cell therapy using TCR-engineered T cells is an exciting area of research and has emerged as a promising strategy for treating cancer patients. However, the effector function of TCR-engineered T cells can be tuned down by local mechanisms of tumour-associated immunosuppression. The potential of cytokines to reverse local immune suppression and enhance tumour immunity has been described in the past. The main aim of this project was to engineer T cell specificity as well as effector cytokine production as a strategy to enhance cancer immunotherapy. This was achieved by combining TCR gene transfer with genetic engineering to achieve IL-12 and IL-27 production in therapeutic T cells. In vitro validation data demonstrated not only an enhanced production of IL-12 and IL-27 by the engineered T cells but also an enhanced effector function upon antigen-specific stimulation. In order to circumvent previously described toxic side effects observed with systemic IL-12 delivery, a tet-regulated gene expression system was utilised to regulate cytokine production by engineered T cells in vivo. Adoptive transfer of TCR-redirected T cells expressing regulated IL-12 in B16F10 melanoma-bearing mice resulted in an enhanced accumulation of transferred CD8+ T cells in the tumour and in a change of the innate immune cell composition in the tumour microenvironment. Importantly, regulated IL-12 delivery resulted in enhanced therapeutic efficacy of the transferred T cells without causing systemic toxicity. IL-27 delivery in engineered T cells also showed some effectiveness when combined with TCR gene therapy, although the therapeutic benefit of IL-27 was inferior to IL-12. The data in this study demonstrate the potency of additional genetic manipulation to tailor the TCR-redirected T cell effector function which can result in a substantial enhancement in their therapeutic efficacy, and thus, enhanced antitumor immune response

Degradation in FPGAs: Monitoring, Modeling and Mitigation

This dissertation targets the transistor aging degradation as well as the associated thermal challenges in FPGAs (since there is an exponential relation between aging and chip temperature). The main objectives are to perform experimentation, analysis and device-level model abstraction for modeling the degradation in FPGAs, then to monitor the FPGA to keep track of aging rates and ultimately to propose an aging-aware FPGA design flow to mitigate the aging

Patient Factors Associaed With Adherence And Change In Cardiac Risk Factors Among Cardiac Rehabilitation Patients In Qatar

Background: cardiovascular disease is the number one killer in Qatar. Cardiac rehabilitation (CR) is a cost-effective model of care shown to reduce cardiovascular morbidity and mortality by 20%. However, it is vastly underutilized with low enrollment and adherence rates. This study aimed to (a) examine the association between number of sessions attended and change in cardiac risk factors after completion of CR program, and (b) investigate factors associated with adherence Methods: This is a retrospective cohort study, consisted of 714 cardiac patients, aged ≥18 years, referred to a cardiac rehabilitation program in Qatar. A simple linear regression analysis (unadjusted model) was used to assess the association between the mean change in each of the following risk factors: cholestrol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and body mass index (BMI and number of sessions attended. Then, we adjusted for clinical and sociodemographic factors that affect the outcome variable via multiple linear regression analyses. Logistic regression model was used to assess factors associated with adherence. Additionally, a paired sample t-test was used to identify mean change in cardiac risk factors pre-post CR and link this change to clinical significant cut off values in the literature. An independent sample t-test was used to identify change between groups (adherence vs. no adherence). Result: The mean age of the population was 52.7±10.1 years (mean ± SD). Patients referred to CR program were mostly males (n= 641, 89.8%) and non-Qatari (n= 596, 83.5%), almost one fourth were smokers (n=185, 25.91%), and one fifth (n=128, 18.8%) were diagnosed with severe depression. The main positive predictor for adherence was AACVPR moderate risk [OR=12.71, 95%CI= 7.81-20.68] and high-risk level [OR=10, 95%CI= 6.44-17.44]. PCI [OR=0.39, 95%CI= 0.17-0.89] and musculoskeletal disease [OR=0.17, 95%CI= 0.03-0.95] were negatively associated with adherence. We found clinically significant improvements among adherents to CR; 10% reduction in total cholesterol level and 15% reduction in low-density lipoproteins. Conclusion: This study provides new insights in Qatar setting into the factors that lead patients to adhere to their CR sessions. These patient-level variables associated with adherence represent opportunities for program directors in identifying patients who are less likely to adhere to the program; therefore, develope effective interventions to target these patients and consequently improve their health status

Zeminlerin Mekanik Davranışının Modellenmesi

Konferans Bildirisi -- Teorik ve Uygulamalı Mekanik Türk Milli Komitesi, 2008Conference Paper -- Theoretical and Applied Mechanical Turkish National Committee, 2008Zemin–yapı etkileşimi problemlerinde, zeminin cinsi, rijitliği ve deformasyon özellikleri çok önemlidir. Araştırmacılar genellikle, üst yapı davranışı üzerinde yoğunlaştıkları için zemin davranışı basite indirgenip, zemin lineer elastik malzeme kabul edilmekte ve sadece elastisite modülü ve Poisson oranı gibi birkaç parametreye ihtiyaç duyulmaktadır. Gerçekte zemin davranışı lineer elastik olmadığı gibi çok karmaşık bir yapıya sahiptir. Bu çalışmada kum zeminler üzerine oturan dairesel temellerin taşıma kapasiteleri laboratuar ortamında küçük ölçekli model deneylerle ve sayısal analiz yöntemleriyle araştırılmıştır. Sonlu elemanlar yöntemine dayalı PLAXIS V.8.2 (Finite Element Code for Soil and Rock Analyses) bilgisayar yazılımı kullanılarak yapılan sayısal analizlerde Lineer Elastik, Mohr Coulomb ve Pekleşme Zemin modelleri kullanılmıştır. Sayısal analiz sonuçları model deney sonuçları ile karşılaştırılmıştır. Sonuçta deneysel verilerle Pekleşme Zemin modeli kullanılarak elde edilen sayısal verilerin birbirleri ile daha uyumlu olduğu gözlenmiş, kum zeminler üzerine oturan dairesel temellerin taşıma kapasitesinin hesabında Pekleşme Zemin modeli parametrelerinin kullanılmasının daha uygun olacağı kanaatine varılmıştır. Ayrıca, Pekleşme Zemin modelinde kullanılan çeşitli parametrelerin (içsel sürtünme açısı, rijitlik modülleri) zemin davranışına etkisi ile ilgili parametrik çalışmalar da yapılmış, sonuçlar yorumlanmaya çalışılmıştır.In soil-structure interaction problems, soil type, soil rigidity and soil deformation characteristics are important. Researchers commonly focused on structure behavior therefore soil behavior is simplified assuming soil as a linear elastic material and need a few parameters such as modulus of elasticity and Poisson’s ratio. In reality, soil behavior is not linear elastic, just the opposite, soil has a very complex structure. In this study, the bearing capacity of circular foundation rested on sandy soils was investigated by small scale model tests in laboratory and numerical analyses. Numerical analyses were performed with a finite element method based computer software program PLAXIS V.8.2 (Finite Element Code for Soil and Rock Analyses) and Linear Elastic, Mohr Coulomb and Hardening Soil models were applied in these numerical analyses. The results of numerical analyses and model test were compared. Eventually, it was observed that results from Hardening Soil model had good agreement with model test results and it was proposed that in sandy soil rested circular foundation’s bearing capacity calculation using Hardening Soil model parameters was most suitable. Additionally, a parametric study concerning with the effect of some Hardening Soil model parameters (friction angle, oedometer and triaxial rigidity modulus) on soil behavior was conducted and the results were discussed

Evaluation of Subgrade Modulus and Bearing Capacity with Large Scale Field Tests on Geogrid-Reinforced Granular Fill over Clay Soil

This study aims at experimentally explaining the potential benefits of geogrid reinforcedsoil foundations using large scale field tests. A total of 8 large scale field tests were carriedout to evaluate the effects of replacing natural clay soil with stronger granular fill layer andsingle-multiple layers of geogrid reinforcement placed into granular fill below circularfootings. The large scale field tests were performed using two different sizes of the circularfooting diameters which have 0.30 and 0.90m. The results of testing program are presented interms of subgrade modulus and bearing capacity. Subgrade modulus and bearing capacityvalues were calculated for each test at settlements of 10, 20 and 30mm.It has been seen that based on the test results, the use of granular fill and geogrid forreinforced soil foundations (RSF) have considerable effects on the subgrade modulus andbearing capacity

Prediction of bearing capacity of circular footings on soft clay stabilized with granular soil

AbstractThe shortage of available and suitable construction sites in city centres has led to the increased use of problematic areas, where the bearing capacity of the underlying deposits is very low. The reinforcement of these problematic soils with granular fill layers is one of the soil improvement techniques that are widely used. Problematic soil behaviour can be improved by totally or partially replacing the inadequate soils with layers of compacted granular fill. The study presented herein describes the use of artificial neural networks (ANNs), and the multi-linear regression model (MLR) to predict the bearing capacity of circular shallow footings supported by layers of compacted granular fill over natural clay soil. The data used in running the network models have been obtained from an extensive series of field tests, including large-scale footing diameters. The field tests were performed using seven different footing diameters, up to 0.90m, and three different granular fill layer thicknesses. The results indicate that the use of granular fill layers over natural clay soil has a considerable effect on the bearing capacity characteristics and that the ANN model serves as a simple and reliable tool for predicting the bearing capacity of circular footings in stabilized natural clay soil

Dynamic Response of a Single Pile Embedded in Sand Including the Effect of Resonance

In this paper, responses of a single pile embedded in sand soil (loose and dense) under dynamic loading (sinusoidal dynamic vibrations of 0.1 g to 0.5 g) have been investigated by two-dimensional analysis using the finite element method (FEM). Viscous (dashpot) boundaries have been used for taking the boundary effects of far-field into account. The applicability and accuracy of site responses of two-dimensional analysis due to the FEM modelling have been well verified with one-dimensional site responses. The results indicate that the relative density of sand (loose, dense) becomes prominent for the displacements of the pile, specifically under the frequency effects of resonance. While the pile in loose sand causes the displacements of 0.1 m to 0.5 m, the pile in dense sand leads to the displacements of 0.05 m to 0.25 m, proportionally with the dynamic loads from 0.1 g to 0.5 g. Moreover, the displacements reach their peak value at the frequency ratio of the resonance case. Viscous boundaries are found sufficient for modelling excessive displacements due to dynamic loading. However, the displacements reveal that high vibrations (> 0.1 g for loose sand, > 0.2 g for dense sand) influencing the pile deformations are critical for the issues of settlements. This is more significant for the resonance case in order for ensuring sufficient design. Consequently, the findings from the study are promising good contributions for pile design under the dynamic effect

3D Numerical Modeling of a Single Pipe Pile Under Axial Compression Embedded in Organic Soil

The objective of this paper is to numerically study the behavior pipe pile under axial compression embedded in organic soil has been numerically predicted. The pipe pile used in the study has been produced by steel and it has outer and inner diameters of 20 mm and 15 mm, respectively. The pile embedded in organic soil, which has the pile length ratios of 10, 20 and 30 (L/D), has been exposed to the axial load for different diameter ratios (d/D = 0, 0.25, 0.50 and 0.75). Numerical analyses have been performed by using Plaxis 3D computer program which is based on finite element method. The capability of the numerical analysis in the prediction of the load capacity of pipe pile has been studied. It has been understood that the results obtained from numerical analysis and experiment are in a good agreement, and then it has been observed in the parametric study that the load capacity of single pipe pile increases with the increase of the pile length and the wall thickness. © 2020, Springer Nature Switzerland AG

An Extension Interface Concept for Multilayered Applications

Extensibility is an important feature of modern software applications. In the context of business applications it is one of the major selection criteria from the customer perspective. Software extensions enable developers to integrate new features to a software system for supporting new requirements. However, there are many open challenges concerning the software provider and the extension developer. A software provider must provide extension interfaces that define the software artifacts of the base application that are allowed to be extended, where and when the extension code will run, and what resources of the base application an extension is allowed to access. While concepts for such interfaces are still a challenging research topic for ``traditional'' software constructed using a single programming language, they are completely missing for complex systems consisting of several abstraction layers. In addition, state-of-the-art approaches do not support providing different extension interfaces for different stakeholders. To develop an extension for a certain software system, the extension developer has to understand what extension possibilities exist, which software artifacts provide these possibilities, the constraints and dependencies between the extensible software artifacts, and how to correctly implement an extension. For example, a simple user interface extension in a business application can require a developer to consider extensible artifacts from underlying business processes, database tables, and business objects. In commercial applications, extension developers can depend on classical means like application programming interfaces, frameworks, documentation, tutorials, and example code provided by the software provider to understand the extension possibilities and how to successfully implement, deploy, and run an extension. For complex multilayered applications, relying on such classical means can be very hard and time-consuming for the extension developers. In integrated development environments, various program comprehension tools and approaches have helped developers in carrying out development tasks. However, most of the tools focus on the code level, lack the support for multilayered applications, and do not particularly focus on extensibility. In this dissertation I aim to provide better means for defining, implementing, and consuming extension interfaces for multilayered applications. I claim that explicit extension interfaces are required for multilayered applications and they are needed for simplifying the implementation (i.e., the concrete realization) and maintainability of extension interfaces on the side of the software provider as well as the consumption of these interfaces by the extension developers. To support this thesis, I first analyze problems with extension interfaces from the perspectives of both the software provider through an example business application and an analysis of a corpus of software systems. I then analyze the problems with the consumption of extension interfaces (i.e., extension development) through a user study involving extension developers performing extension development tasks for a complex business application. Next, I present XPoints, an approach and a language for the specification of extension possibilities for multilayered applications. I develop an instantiation of XPoints evaluate it against current state-of-the-art works and its usability through a user study. I finally show how XPoints can be applied to simplify the extension development through the implementation of a recommender system for extension possibilities for multilayered applications. The advantages of the recommender system are illustrated through an example as well through a comparison between the current state-of-the-art tools for program comprehension. Topics like extension validation, monitoring, and conflict detection are left for future work