Prognostic and predictive value of liquid biopsy-derived androgen receptor variant 7 (AR-V7) in prostate cancer : a systematic review and meta-analysis

In advanced prostate cancer, access to recent diagnostic tissue samples is restricted and this affects the analysis of the association of evolving biomarkers such as AR-V7 with metastatic castrate resistance. Liquid biopsies are emerging as alternative analytes. To clarify clinical value of AR-V7 detection from liquid biopsies, here we performed a meta-analysis on the prognostic and predictive value of androgen receptor variant 7 (AR-V7) detected from liquid biopsy for patients with prostate cancer (PC), three databases, the Embase, Medline, and Scopus were searched up to September 2021. A total of 37 studies were included. The effects of liquid biopsy AR-V7 status on overall survival (OS), radiographic progression-free survival (PFS), and prostate-specific antigen (PSA)-PFS were calculated with RevMan 5.3 software. AR-V7 positivity detected in liquid biopsy significantly associates with worse OS, PFS, and PSA-PFS (P <0.00001). A subgroup analysis of patients treated with androgen receptor signaling inhibitors (ARSi such as abiraterone and enzalutamide) showed a significant association of AR-V7 positivity with poorer OS, PFS, and PSA-PFS. A statistically significant association with OS was also found in taxane-treated patients (P = 0.04), but not for PFS (P = 0.21) or PSA-PFS (P = 0.93). For AR-V7 positive patients, taxane treatment has better OS outcomes than ARSi (P = 0.01). Study quality, publication bias and sensitivity analysis were integrated in the assessment. Our data show that liquid biopsy AR-V7 is a clinically useful biomarker that is associated with poor outcomes of ARSi-treated castrate resistant PC (CRPC) patients and thus has the potential to guide patient management and also to stratify patients for clinical trials. More studies on chemotherapy-treated patients are warranted. Systematic Review Registration: PROSPERO, CRD42021239353

Sintesis dan Karakterisasi TiO2-Karbon Aktif Tempurung Kelapa sebagai Photocatalyst Agent dalam Pengolahan Limbah Cair Batik

Produksi industri batik banyak menggunakan bahan kimia dan pewarna sintetis dalam proses produksinya. Limbah cair yang dihasilkan, apabila tidak diolah akan menyebabkan pencemaran lingkungan. Salah satu metode alternatif dalam pengolahan limbah cair batik yaitu metode fotokatalis. Kelebihan metode fotokatalis yaitu dapat mendegradasi bahan anorganik dan bahan organik, biaya operasi yang rendah dan ramah lingkungan. Penelitihan ini bertujuan sintesis dan karakterisasi TiO2/C sebagai photocatalyst agent dalam pengolahan limbah cair batik. Karakterisasi yang digunakan meliputi pengujian kualitas arang aktif teknis, FTIR, dan XRD. Kualitas karbon aktif telah memenuhi (SNI) 06-3730-1995 tentang syarat mutu karbon aktif teknis powder. Pengujian XRD dari hasil sintesis didapatkan TiO2 tipe anatase. Hasil pengujian FTIR karbon aktif terbaca gugus fungsi O-H, C=C, C-O dan gugus C-C. FTIR TiO2 dan sintesis TiO2/C terbaca gugus Ti-O-C dan Ti-O-Ti

An Analysis of Laboratory Inspections at the University of Kentucky

Recent news stories about laboratory accidents in which students were severely injured and killed have brought much-needed attention to lab safety. Creating a positive safety climate on college and university campuses is very important in reducing accidents. At the University of Kentucky, all laboratories are inspected once every year, and the results are recorded in a lab inspection database. These data include the department, building, lab classification, type of violation, room number, and the name of the PI (Principal Investigator). I want to analyze inspections to find out whether department and the lab classification are significant in looking at violations. Knowing this will help safety officials provide better, more specific training to those who work in these areas, and will provide those in authority with better tools to reach people at the most appropriate level. Violations can be looked at as potential accidents and potential fines. Acting on the findings of these inspections is crucial in preventing accidents from occurring on campus. In looking at the idea of safety climate, I considered which available variables would be best to reach this concept. I thought about using building, but it is collinear with department. Departments to some extent share space in a building. Multiple departments may be housed in a building, or one department may be split between a couple of buildings. If I used this and department, my results would be difficult to interpret Departments are under the same leadership, and lab inspection reports are distributed to department chairs as well as the PI, and other safety officials. Lab classification is important because it defines the storage and use of chemicals in that lab facility. There are four lab classifications that range from broad use and storage of chemicals to no use or storage of hazardous chemicals. There are no data on specific chemicals used, or the type of experiments that are conducted. Looking at the classification was also the best way to look at potential risk with the available data. The question I hope to answer is: Do department and classification of labs affect the likelihood of violations? I looked at the average violations per inspection by department. I also looked at the average violations per inspection by classification. Fixed effects and random affects regressions were run with inspections as the unit of analysis, looking at classification and department. According to the regression, the null hypothesis that lab classification is unrelated to the number of violations can be rejected. The P-values are less than 0.05, which makes lab classifications statistically significant. The results indicate that the laboratories that are equipped to handle the most hazardous chemicals are more likely to have violations, whereas the laboratories that are more restricted in the use of chemicals have fewer violations. This may simply occur because there is greater risk in a laboratory where there is broad use of chemicals, as opposed to those where chemicals are simply to be stored. The coefficient increases steadily along with the classification of the lab. This reinforces the finding that labs that are equipped to handle more chemicals are more likely to have violations. Department is also an important indicator of violations. Even when the classification is accounted for, violations per department are statistically and managerially significant and vary by more than 0.5 violations above and below a mean 0.678 violations per lab. This finding would allow further investigation and targeted training to departments that need it. I would also like to know more about the type of violations by department, to learn more about trends or possible causes. The Occupational Health and Safety Department (OHS) at UK has no authority to force labs to address any violations. Department chairs, any safety officials they designate, and most importantly, the Vice President of Research has enforcement authority. There must be procedures in place at the departmental level to ensure a commitment to safety that is perceived by employees and practiced in their daily work. Safety must be easily accessible to all employees. Proper equipment, information, and a climate where safety is the main priority are crucial. I recommend that the Vice President of Research receive a quarterly report of inspections by department and lab classification from OHS, since he has the authority to enforce lab inspection findings, and it is in his interest to make sure no accidents occur, and no fines are assessed to the University by the Occupational Safety and Health Administration (OSHA), the government agency that sets the standard for occupational exposure to hazardous chemicals in laboratories. Department chairs and PIs already receive the inspections, but having additional oversight may improve the departments who rank lower in their inspections. Because reporting at the departmental level has significance, a simplified report can be created rather than one that lists the results of every inspection on campus

Analysis of AR/AR-V7signalling pathways in circulating tumour cells of prostate cancer patients

Biomarkers detected in liquid biopsy (such as circulating tumour cells, CTCs) demonstrate high concordance with biomarkers detected in conventional tissue biopsy. Prostate cancer, when metastatic, is treated with androgen deprivation therapy (ADT). However, resistance to ADT evolves into a clinical state referred to as castrate resistant prostate cancer (CRPC), in which increased, abnormal, androgen receptor (AR) signalling through changed AR structures (amplification, point mutations or variant expression) occurs. Although CRPC also facilitates development of other, complex signalling pathways that promote cell survival, our hypothesis is that the abnormal AR signalling is tightly linked to PTEN/AKT and Hippo/YAP pathways that contribute to the oncogenic driver role that confers ADT resistance. This PhD project aims to evaluate the role of AR, PTEN, and Hippo driver pathways in CRPC through analysis of CTCs, which have become important biological correlates and sources to study tumour biology in prostate cancer. The main focus was on the AR splice variant 7 (ARV7), a promising predictive and prognostic CRPC biomarker. The overall outcomes of this PhD project were to (i) investigate the role of AR, PTEN, and Hippo pathways implicated in CRPC, (ii) validate liquid-biopsy-detected AR-V7 as a CRPC biomarker, (iii) define the best antibody to detect AR-V7 CTCs in CRPC patient blood, and (iv) optimise methods that enable multiplex immunocytostaining of prostate cancer cells, including CTCs with a view to conduct ‘proteomic microscopy’ in the future. This work in this PhD puts in place basic procedures and methods that will enable CTC multiplex “proteomic microscopy” a method that could change the current paradigm of CTC analysis by allowing analysis of these rare cells for multiple markers targeting multiple biological pathways at the same time

Security of electric power systems : cascading outage analysis, interdiction model and resilience to natural disasters

textSecure electric power system operation is key to social warfare. However, recent years have seen numerous natural disasters and terrorist attacks that threat the grid security. This dissertation summarizes the efforts to develop a model to analyze cascading outages, an interdiction model to analyze worst-case attacks on power grids, and research on grid resilience to natural disasters. The developed cascading outage analysis model uses outage checkers to systematically simulate the system behavior after an initial disturbance, and calculate the potential cascading outage path and electric load shedding. The new interdiction model combines the previously developed medium-term attack-defense model with the short-term cascading outage analysis model to find worst-case terrorist attack. The dissertation also reviews the research on power grid resilience to natural disaster, and develops a framework to simulate the impacts of hurricanes.Electrical and Computer Engineerin

Event-B in the Institutional Framework: Defining a Semantics, Modularisation Constructs and Interoperability for a Specification Language

Event-B is an industrial-strength specification language for verifying the properties of a given system’s specification. It is supported by its Eclipse-based IDE, Rodin, and uses the process of refinement to model systems at different levels of abstraction. Although a mature formalism, Event-B has a number of limitations. In this thesis, we demonstrate that Event-B lacks formally defined modularisation constructs. Additionally, interoperability between Event-B and other formalisms has been achieved in an ad hoc manner. Moreover, although a formal language, Event-B does not have a formal semantics. We address each of these limitations in this thesis using the theory of institutions. The theory of institutions provides a category-theoretic way of representing a formalism. Formalisms that have been represented as institutions gain access to an array of generic specification-building operators that can be used to modularise specifications in a formalismindependent manner. In the theory of institutions, there are constructs (known as institution (co)morphisms) that provide us with the facility to create interoperability between formalisms in a mathematically sound way. The main contribution of this thesis is the definition of an institution for Event-B, EVT, which allows us to address its identified limitations. To this end, we formally define a translational semantics from Event- B to EVT. We show how specification-building operators can provide a unified set of modularisation constructs for Event-B. In fact, the institutional framework that we have incorporated Event-B into is more accommodating to modularisation than the current state-of-the-art for Rodin. Furthermore, we present institution morphisms that facilitate interoperability between the respective institutions for Event-B and UML. This approach is more generic than the current approach to interoperability for Event-B and in fact, allows access to any formalism or logic that has already been defined as an institution. Finally, by defining EVT, we have outlined the steps required in order to include similar formalisms into the institutional framework. Hence, this thesis acts as a template for defining an institution for a specification language

Agoric computation: trust and cyber-physical systems

In the past two decades advances in miniaturisation and economies of scale have led to the emergence of billions of connected components that have provided both a spur and a blueprint for the development of smart products acting in specialised environments which are uniquely identifiable, localisable, and capable of autonomy. Adopting the computational perspective of multi-agent systems (MAS) as a technological abstraction married with the engineering perspective of cyber-physical systems (CPS) has provided fertile ground for designing, developing and deploying software applications in smart automated context such as manufacturing, power grids, avionics, healthcare and logistics, capable of being decentralised, intelligent, reconfigurable, modular, flexible, robust, adaptive and responsive. Current agent technologies are, however, ill suited for information-based environments, making it difficult to formalise and implement multiagent systems based on inherently dynamical functional concepts such as trust and reliability, which present special challenges when scaling from small to large systems of agents. To overcome such challenges, it is useful to adopt a unified approach which we term agoric computation, integrating logical, mathematical and programming concepts towards the development of agent-based solutions based on recursive, compositional principles, where smaller systems feed via directed information flows into larger hierarchical systems that define their global environment. Considering information as an integral part of the environment naturally defines a web of operations where components of a systems are wired in some way and each set of inputs and outputs are allowed to carry some value. These operations are stateless abstractions and procedures that act on some stateful cells that cumulate partial information, and it is possible to compose such abstractions into higher-level ones, using a publish-and-subscribe interaction model that keeps track of update messages between abstractions and values in the data. In this thesis we review the logical and mathematical basis of such abstractions and take steps towards the software implementation of agoric modelling as a framework for simulation and verification of the reliability of increasingly complex systems, and report on experimental results related to a few select applications, such as stigmergic interaction in mobile robotics, integrating raw data into agent perceptions, trust and trustworthiness in orchestrated open systems, computing the epistemic cost of trust when reasoning in networks of agents seeded with contradictory information, and trust models for distributed ledgers in the Internet of Things (IoT); and provide a roadmap for future developments of our research

2020 Program and Abstracts for the Celebration of Student Scholarship

Program and Abstracts from the Celebration of Student Scholarship held in the Spring of 2020

The combinatorics of minimal unsatisfiability: connecting to graph theory

Minimally Unsatisfiable CNFs (MUs) are unsatisfiable CNFs where removing any clause destroys unsatisfiability. MUs are the building blocks of unsatisfia-bility, and our understanding of them can be very helpful in answering various algorithmic and structural questions relating to unsatisfiability. In this thesis we study MUs from a combinatorial point of view, with the aim of extending the understanding of the structure of MUs. We show that some important classes of MUs are very closely related to known classes of digraphs, and using arguments from logic and graph theory we characterise these MUs.Two main concepts in this thesis are isomorphism of CNFs and the implica-tion digraph of 2-CNFs (at most two literals per disjunction). Isomorphism of CNFs involves renaming the variables, and flipping the literals. The implication digraph of a 2-CNF F has both arcs (¬a → b) and (¬b → a) for every binary clause (a ∨ b) in F .In the first part we introduce a novel connection between MUs and Minimal Strong Digraphs (MSDs), strongly connected digraphs, where removing any arc destroys the strong connectedness. We introduce the new class DFM of special MUs, which are in close correspondence to MSDs. The known relation between 2-CNFs and implication digraphs is used, but in a simpler and more direct way, namely that we have a canonical choice of one of the two arcs. As an application of this new framework we provide short and intuitive new proofs for two im-portant but isolated characterisations for nonsingular MUs (every literal occurs at least twice), both with ingenious but complicated proofs: Characterising 2-MUs (minimally unsatisfiable 2-CNFs), and characterising MUs with deficiency 2 (two more clauses than variables).In the second part, we provide a fundamental addition to the study of 2-CNFs which have efficient algorithms for many interesting problems, namely that we provide a full classification of 2-MUs and a polytime isomorphism de-cision of this class. We show that implication digraphs of 2-MUs are “Weak Double Cycles” (WDCs), big cycles of small cycles (with possible overlaps). Combining logical and graph-theoretical methods, we prove that WDCs have at most one skew-symmetry (a self-inverse fixed-point free anti-symmetry, re-versing the direction of arcs). It follows that the isomorphisms between 2-MUs are exactly the isomorphisms between their implication digraphs (since digraphs with given skew-symmetry are the same as 2-CNFs). This reduces the classifi-cation of 2-MUs to the classification of a nice class of digraphs.Finally in the outlook we discuss further applications, including an alter-native framework for enumerating some special Minimally Unsatisfiable Sub-clause-sets (MUSs)

Standing in the intersection : using Photovoice to understand the lived experience of black gay college students attending predominantly white postsecondary institutions.

The intersection of multiple oppressed identities is characterized by the compounded effects of victimization, intimidation and continued marginalization by dominant culture groups in society. Despite a growing body of knowledge about the individual experiences of racial and sexual minorities, there remains a lack of understanding of the unique life experiences of individuals with intersecting oppressed identities, specifically Black gay youth. Failure or inability to recognize, understand and take action in response to the needs of Black gay youth in college, perpetuates a culture of oppression that compromises the physical and mental well-being, and the academic success of these students. Engaging Black gay college students in a Photovoice project affords said students the opportunity to document their everyday experiences in photographic images, tell the stories of their lives, and identify the strengths and needs of their community for campus policy makers, educators, practitioners and researchers. While it represents a trusted approach in understanding the lived experiences of marginalized and oppressed people, Wang and Burris’ (1994) participatory action research method Photovoice is underutilized as a means of understanding the lived experience of Black gay college students. This dissertation study utilized a modified Photovoice project as well as other qualitative and quantitative research methods to explore the lived experience of Black gay college students, the meaning they attribute to said experiences and subsequent role performance. The students in this study demonstrated a keen awareness of the complexity and compounded effects of their identities and resilience in the face of harassment and repeated microaggressions while identifying and employing multiple pathways to personal, academic and professional success